記述言語：英語   掲載種別：研究論文（学術雑誌）  

The purpose of this study was to evaluate the effects of administration of overnight 1 mg dexamethasone on vascular function in patients with nonfunctioning adrenal adenomas (NFA). Flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID) were measured to assess vascular function in 22 patients with NFA who had hypertension and/or diabetes mellitus (DM) and 272 patients without adrenal incidentalomas who had hypertension and/or DM (control patients with hypertension and/or DM). FMD and NID were measured in the morning before and after administration of 1 mg of dexamethasone at 2300 h in 18 patients with NFA. There were no significant differences in FMD and NID between control patients with hypertension and/or DM and patients with NFA who had hypertension and/or DM (3.4 ± 2.8% vs. 2.9 ± 1.9% and 11.5 ± 5.7% vs. 11.4 ± 4.3%, P = 0.46, and P = 0.99, respectively). There were no significant differences in vascular function between control patients with hypertension and/or DM and patients with NFA who had hypertension and/or DM even after adjustment for cardiovascular risk factors. Overnight 1 mg dexamethasone increased FMD from 2.4 ± 1.9% to 5.3 ± 3.2% (P < 0.01) and increased NID from 12.1 ± 4.2% to 14.0 ± 2.8% (P < 0.01) in patients with NFA. The overnight 1 mg dexamethasone suppression test does not impair FMD and NID in patients with NFA. Decreases in circulating levels of cortisol may improve vascular function.Clinical Trial Registration: This study was approved by principal authorities and ethical issues in Japan (URL for Clinical Trial: http://www.umin.ac.jp/ctr/index.htm Registration Number for Clinical Trial: UMIN000039512).

DOI： 10.1038/s41598-023-48295-y

PubMed

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s13287-023-03553-8

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cardiovascular mortality has been shown to vary seasonally. However, it has not been determined whether vascular function is affected by the season. The purpose of this study was to investigate the associations of vascular function with season and outdoor temperature. Between April 2007 and March 2022, measurements of flow-mediated vasodilation (FMD) of the brachial artery as an index of endothelial function and nitroglycerine-induced vasodilation (NID) as an index of endothelium-independent vasodilation were performed in 2190 subjects. There was no significant seasonal difference in FMD (spring, 3.9 ± 3.1%; summer, 3.5 ± 3.0%; fall, 3.7 ± 3.0%; winter, 3.6 ± 3.2%; P = 0.14). There was no significant correlation between FMD and daily mean outdoor temperature (r = -0.02, P = 0.25). Multivariate analyses revealed that neither season (β = -0.020, P = 0.31) nor outdoor temperature (β = 0.005, P = 0.81) was significantly associated with FMD after adjustment for other confounding factors. There were significant seasonal differences in NID (spring, 12.8 ± 6.3%; summer, 12.0 ± 6.1%; fall, 11.7 ± 6.1%; winter, 12.3 ± 5.9%; P = 0.02). However, multivariate analysis revealed that there was no significant association between season and NID after adjustment for other confounding factors (β = -0.012, P = 0.56). There was no significant correlation between NID and daily outdoor mean temperature (r = -0.03, P = 0.17). Multivariate analysis revealed that outdoor temperature was not significantly associated with NID (β = -0.006, P = 0.78). There was no significant association of FMD or NID with season or outdoor temperature, suggesting that it is not necessary to take into account the effects of season and outdoor temperature on vascular function when interpreting the results of FMD and NID measurements. Public trials registry number: UMIN000039512.

DOI： 10.1038/s41440-023-01504-7

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: There is little information on the relationships of serum small dense low-density lipoprotein cholesterol (sdLDL-C) levels and serum triglyceride (TG) levels with cardiovascular events in patients with coronary artery disease (CAD) and type 2 diabetes mellitus (DM) who are receiving statins. The aim of this study was to evaluate the relationships of serum TG levels and sdLDL-C levels as residual risks for cardiovascular events in patients with CAD and type 2 DM who were being treated with statins. METHODS: The subjects were divided into four groups based on TG levels and sdLDL-C levels: sdLDL-C of ＜40.0 mg/dL and TG of ＜150 mg/dL, sdLDL-C of ≥ 40.0 mg/dL and TG of ＜150 mg/dL, sdLDL-C of ＜40.0 mg/dL and TG of ≥ 150 mg/dL, and sdLDL-C of ≥ 40.0 mg/dL and TG of ≥ 150 mg/dL. During a median follow-up period of 1419 days, cardiovascular events occurred in 34 patients. RESULTS: The incidences of cardiovascular events were significantly higher in patients with sdLDL-C of ≥ 40.0 mg/dL and TG of ＜150 mg/dL and in patients with sdLDL-C of ≥ 40.0 mg/dL and TG of ≥ 150 mg/dL, but not in patients with sdLDL-C of ＜40.0 mg/dL and TG of ≥ 150 mg/dL, than in patients with sdLDL-C of ＜40.0 mg/dL and TG of ＜150 mg/dL. CONCLUSIONS: Under the condition of treatment with statins, patients with CAD and type 2 DM who had sdLDL-C levels of ≥ 40.0 mg/dL had a high risk for cardiovascular events even though serum TG levels were controlled at ＜150 mg/dL.

DOI： 10.5551/jat.64416

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Low-intensity pulsed ultrasound (LIPUS) irradiation has been shown to induce various responses in different cells. It has been shown that LIPUS activates extracellular signal-regulated kinase 1/2 (ERK1/2) through integrin. PURPOSE: To study the effects of LIPUS on myogenic regulatory factors and other related myogenesis elements in a volumetric skeletal muscle loss injury model. STUDY DESIGN: Controlled laboratory study. METHODS: C57BL/6J mice were subjected to full-thickness muscle defect injury of the quadriceps and treated with direct application of LIPUS 20 min/d or non-LIPUS treatment (control) for 3, 7, and 14 days. LIPUS was also applied to C2C12 cells in culture in the presence of low and high doses of lipopolysaccharides. The expression levels of myogenic regulatory factors and the expression levels of myokine-related and angiogenic-related proteins of the control and LIPUS groups were analyzed. RESULTS: Muscle volume in the injury site was restored at day 14 with LIPUS treatment. Paired-box protein 7, myogenic factor 5, myogenin, and desmin expressions were significantly different between control and LIPUS groups at days 7 and 14. Myokine and angiogenic cytokine-related factors were significantly increased in the LIPUS group at day 3 and decreased with no significant difference between the groups by day 14. LIPUS induced different responses of myogenic regulatory factors in C2C12 cells with low and high doses of lipopolysaccharides. LIPUS promoted myogenesis through short-lived increase in interleukin-6 and heme oxygenase 1, together with activation of ERK1/2. CONCLUSION: LIPUS had a constant effect on the variables of tissue damage, from macrotrauma to microtrauma, leading to efficient muscle regeneration. CLINICAL RELEVANCE: The focus of therapeutic strategies with LIPUS has been not only for microvascular regeneration but also for skeletal muscle and related local tissue recovery from acute or chronic damage.

DOI： 10.1177/03635465231195850

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The percentage of mean arterial pressure (%MAP) is the height of the mean arterial waveform divided by the peak amplitude of the waveform of pulse volume recording. The purpose of this study was to determine whether the cutoff value of 45% for %MAP at the ankle, which is recommended for the diagnosis of lower extremity artery disease, in combination with ankle-brachial index (ABI) is useful for detecting patients with clinical coronary artery disease (CAD) and investigate the optimal cutoff value of %MAP to diagnose patients with CAD. We measured ABI and %MAP in 2213 subjects (mean age: 61.2 ± 15.5 years). Multivariate analysis revealed that %MAP ≥ 45% was significantly associated with a higher risk of CAD after adjusting for traditional cardiovascular risk factors (odds ratio [OR], 2.14; 95% confidence interval [CI], 1.43-3.21; p < 0.001). However, the association was no longer significant after adjusting for ABI (OR, 1.39; 95% CI, 0.83-2.33; p = 0.21), whereas ABI was significantly associated with CAD (OR, 0.98; 95% CI, 0.97-0.99; p = 0.005). The optimal cutoff value of %MAP derived from a receiver operating characteristic curve to diagnose CAD was 40.3%. Multivariate analysis revealed that %MAP ≥ 40.3% was significantly associated with a higher risk of CAD (OR, 1.63; 95% CI, 1.19-2.24; p = 0.002) independent of ABI (OR, 0.98; 95% CI, 0.97-0.99; p = 0.002). The cutoff value of 40.3%, but not 45%, for %MAP may be useful for detecting patients with advanced atherosclerosis and for cardiovascular risk assessment independent of ABI. REGISTRATION INFORMATION: http://www.umin.ac.jp (University Hospital Medical Information Network Clinical Trials Registry) (UMIN000039512).

DOI： 10.1038/s41440-023-01442-4

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The relationship of KCNJ5 mutation with vascular function and vascular structure in aldosterone-producing adenoma (APA) patients before and after adrenalectomy remains unclear. The purpose of this study was to evaluate the influence of KCNJ5 mutation on vascular function and vascular structure in APA and the effects of adrenalectomy on vascular function and vascular structure in APA patients with and those without KCNJ5 mutation. Flow-mediated vasodilation (FMD), nitroglycerine-induced vasodilation (NID), brachial artery intima-media thickness (IMT), and brachial-ankle pulse wave velocity (baPWV) were measured to assess vascular function and vascular structure in 46 APA patients with KCNJ5 mutation and 23 APA patients without KCNJ5 mutation and in 69 matched pairs of patients with essential hypertension (EHT). FMD, NID, brachial IMT and baPVW were evacuated before adrenalectomy and at 12 weeks after adrenalectomy in APA patients with KCNJ5 mutation and APA patients without KCNJ5 mutation. FMD and NID were significantly lower in APA patients than in patients with EHT. There was no significant difference in FMD or NID between patients with and those without KCNJ5 mutation. In APA patients with KCNJ5 mutation, FMD and NID after adrenalectomy were significantly higher than those before adrenalectomy. In APA patients without KCNJ5 mutation, only NID after adrenalectomy was significantly higher than that before adrenalectomy. Endothelial function in APA patients with KCNJ5 mutation was improved by adrenalectomy in the early postoperative period. KCNJ5 mutation is a predictor for early resolution of endothelial function by adrenalectomy. This study was approved by principal authorities and ethical issues in Japan (URL for Clinical Trial: http://www.umin.ac.jp/ctr/index.htm Registration Number for Clinical Trial: UMIN000003409).

DOI： 10.1038/s41440-023-01375-y

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Our previous work indicated the greater magnitude of damage to the thoracic aorta at 6 months after starting 5 Gy irradiation in descending order of exposure to X-rays in 25 fractions > acute X-rays > acute γ-rays > X-rays in 100 fractions ≫ chronic γ-rays, in which the limitations of the study included a lack of data for fractionated γ-ray exposure. To better understand effects of dose protraction and radiation quality, the present study examined changes after exposure to γ-rays in 25 fractions, and compared its biological effectiveness with five other irradiation regimens. MATERIALS AND METHODS: Male C57BL/6J mice received 5 Gy of 137Cs γ-rays delivered in 25 fractions spread over six weeks. At 6 months after starting irradiation, mice were subjected to echocardiography, followed by tissue sampling. The descending thoracic aorta underwent scanning electron microscopy, immunofluorescence staining and histochemical staining. The integrative analysis of multiple aortic endpoints was conducted for inter-regimen comparisons. RESULTS: Exposure to γ-rays in 25 fractions induced vascular damage (evidenced by increases in endothelial detachment and vascular endothelial cell death, decreases in endothelial waviness, CD31, endothelial nitric oxide synthase and vascular endothelial cadherin), inflammation (evidenced by increases in tumor necrosis factor α, CD68 and F4/80) and fibrosis (evidenced by increases in transforming growth factor β1, alanine blue stain and intima-media thickness). The integrative analysis revealed biological effectiveness in descending order of exposure to X-rays in 25 fractions > acute X-rays > γ-rays in 25 fractions > acute γ-rays > X-rays in 100 fractions ≫ chronic γ-rays. CONCLUSIONS: The results suggest that dose protraction effects on aortic damage depend on radiation quality, and are not a simple function of dose rate and the number of fractions.

DOI： 10.1080/09553002.2023.2242939

PubMed

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Fibrosis is a common histological feature in the process from chronic organ injury to organ failure. Chronic tissue injury causes inflammatory cell infiltration into the injured tissue. The persistence of this inflammatory cell infiltration leads to fibrosis and organ failure. Adipose-derived mesenchymal stem cells (ASCs) have received much attention as a regenerative therapeutic tool to prevent progression from organ injury to failure. Subcutaneous abdominal adipose tissue is divided into superficial and deep layers by a superficial fascia. Adipose tissue easily collected by liposuction is usually obtained from a deep layer, so ASCs derived from a deep layer are generally used for regenerative medicine. However, no research has been conducted to investigate differences in the therapeutic effects of ASCs from the superficial and deep layers (Sup-ASCs and Deep-ASCs, respectively). Therefore, we compared the therapeutic potencies of Sup-ASCs and Deep-ASCs. METHODS: ASCs were isolated from superficial and deep subcutaneous abdominal adipose tissues collected from patients who underwent breast reconstruction. We first compared cell characteristics, such as morphology, cell proliferation, cell surface markers, adipogenic and osteogenic differentiation, cell senescence markers, and expression of coagulation and anticoagulant factors between Sup-ASCs and Deep-ASCs. Furthermore, we compared their ability to promote polarization of M2 macrophages and to inhibit transforming growth factor (TGF)-β/Smad signaling using THP-1 cells and TGF-β1 stimulated HK-2 cells incubated with conditioned media from Sup-ASCs or Deep-ASCs. In in vivo experiments, after renal ischemia-reperfusion injury (IRI) procedure, Sup-ASCs or Deep-ASCs were injected through the abdominal aorta. At 21 days post-injection, the rats were sacrificed and their left kidneys were collected to evaluate fibrosis. Finally, we performed RNA-sequencing analysis of Sup-ASCs and Deep-ASCs. RESULTS: Sup-ASCs had greater proliferation and adipogenic differentiation compared with Deep-ASCs, whereas both ASC types had similar morphology, cell surface markers, senescence markers, and expression of coagulation and anticoagulant factors. Conditioned media from Sup-ASCs and Deep-ASCs equally promoted polarization of M2 macrophages and suppressed TGF-β/Smad signaling. Moreover, administration of Sup-ASCs and Deep-ASCs equally ameliorated renal fibrosis induced by IRI in rats. RNA-sequencing analysis revealed no significant difference in the expression of genes involved in anti-inflammatory and anti-fibrotic effects between Sup-ASCs and Deep-ASCs. CONCLUSIONS: These results indicate that both Sup-ASCs and Deep-ASCs can be used effectively and safely as an intravascular ASC therapy for organ injury.

DOI： 10.1186/s13287-023-03350-3

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The effect of dialytic modality at the start of renal replacement therapy on prognosis is controversial. METHODS: This multicenter, prospective cohort study included patients undergoing incident hemodialysis (HD) (n = 646) and peritoneal dialysis (PD) (n = 72). We excluded patients who lacked complete data for 3 months. One-to-one propensity score (PS) matching was performed before between-group comparison of survival rates (Kaplan-Meier method and log-rank test) and identification of factors affecting prognosis (Cox proportional-hazards regression analysis). RESULTS: We enrolled 621 and 71 patients undergoing HD and PD, respectively (overall mean ± standard deviation age: 74 ± 13 years); 20% had cardiovascular disease (CVD). The median follow-up period was 41 (interquartile range 24-66) months. Following PS matching, we analyzed 65 patients undergoing HD and PD each. The 5-year overall survival rates did not differ between the groups (P = 0.97). The PD group exhibited a better CVD-related survival rate (P = 0.03). PD yielded adjusted hazard ratios for all-cause and CVD-related mortality of 0.99 (95% confidence interval [CI] 0.49-1.99, P = 0.97) and 3.92 (95% CI 1.05-14.7, P = 0.04), respectively. Age (P < 0.001) and the use of a central venous catheter (CVC) at dialytic initiation (P = 0.02) were independent risks for all-cause mortality; whereas, only the use of a CVC (P = 0.01) was an independent risk for CVD-related mortality. CONCLUSION: Although no differences were observed in overall survival, CVD-related survival may be better with dialytic initiation with PD than with HD.

DOI： 10.1007/s10157-023-02315-3

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Heart failure (HF) is associated with endothelial dysfunction. Vascular function per se plays an important role in cardiac function, whether it is a cause or consequence. However, there is no information on vascular function in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM). The purpose of this study was to evaluate vascular function in patients with ATTRwt-CM. We measured flow-mediated vasodilation (FMD) as an index of endothelial function and nitroglycerine-induced vasodilation (NID) as an index of vascular smooth muscle function and brachial artery intima-media thickness (bIMT) and brachial-ankle pulse wave velocity (baPWV) as indices of arterial stiffness in 22 patients with ATTRwt-CM and in 22 one-by-one matched control patients using vascular function confounding factors. FMD was significantly greater in patients with ATTRwt-CM than in the controls (5.4 ± 3.4% versus 3.5 ± 2.4%, p = 0.038) and the N-terminal pro-brain natriuretic peptide (NT-proBNP) level was significantly greater in patients with ATTRwt-CM than in the controls (2202 ± 1478 versus 470 ± 677 pg/mL, p < 0.001). There were no significant differences in NID, bIMT or baPWV between the two groups. There was a significant relationship between NT-proBNP and FMD in patients with ATTRwt-CM (r = 0.485, p = 0.022). NT-proBNP showed no significant relationships with NID, bIMT or baPWV. Conclusions: Endothelial function was preserved in patients with ATTRwt-CM. Patients with ATTRwt-CM may have compensatory effects with respect to endothelial function through elevation of BNP.

DOI： 10.3390/jcm12072534

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The purpose of this study was to evaluate the effects of exposure to radiation caused by an atomic bomb in atomic bomb survivors on vascular function and vascular structure and to evaluate the relationships of radiation dose from the atomic bomb with vascular function and vascular structure in atomic bomb survivors. METHODS: Flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID) as indices of vascular function, brachial-ankle pulse wave velocity (baPWV) as an index of vascular function and vascular structure, and brachial artery intima-media thickness (IMT) as an index of vascular structure were measured in 131 atomic bomb survivors and 1,153 control subjects who were not exposed to the atomic bomb. Ten of the 131 atomic bomb survivors with estimated radiation dose in a cohort study of Atomic Bomb Survivors in Hiroshima were enrolled in the study to evaluate the relationships of radiation dose from the atomic bomb with vascular function and vascular structure. RESULTS: There was no significant difference in FMD, NID, baPWV, or brachial artery IMT between control subjects and atomic bomb survivors. After adjustment of confounding factors, there was still no significant difference in FMD, NID, baPWV, or brachial artery IMT between control subjects and atomic bomb survivors. Radiation dose from the atomic bomb was negatively correlated with FMD (ρ = -0.73, P = 0.02), whereas radiation dose was not correlated with NID, baPWV or brachial artery IMT. CONCLUSION: There were no significant differences in vascular function and vascular structure between control subjects and atomic bomb survivors. Radiation dose from the atomic bomb might be negatively correlated with endothelial function.

DOI： 10.3389/fcvm.2023.1122794

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Klotho is an anti-aging, single-pass transmembrane protein found mainly in the kidney. Although aging is likely to be associated with DNA damage, the involvement of Klotho in protecting cells from DNA damage is still unclear. In this study, we examined DNA damage in human kidney cells and mouse kidney tissue after ionizing radiation (IR). The depletion and overexpression of Klotho in human kidney cells reduced and increased the cell survival rates after IR, respectively. The formation of γ-H2AX foci, representing DNA damage, was significantly elevated immediately after IR in cells with Klotho depletion and decreased in cells overexpressing Klotho. These results were confirmed in mouse renal tissues after IR. Quantification of DNA damage by a comet assay revealed that the Klotho knockdown significantly increased the amount of DNA damage immediately after IR, suggesting that Klotho protects chromosomal DNA from the induction of damage, rather than facilitating DNA repair. Consistent with this notion, Klotho was detected in both the nucleus and cytoplasm. In the nucleus, Klotho may serve to protect chromosomal DNA from damage, leading to its anti-aging effects.

DOI： 10.1093/jb/mvad001

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

We divided the 466 subjects into two groups based on information on sitting time on a non-working day and evaluated flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID). FMD was smaller in subjects with sitting time on a non-working day of ≥6 h/day than in subjects with sitting time on a non-working day of &lt;6 h/day (2.5 ± 2.6% vs. 3.7 ± 2.9%; p &lt; 0.001). NID was smaller in subjects with sitting time at non-working day of ≥ 8 h/day than in subjects with sitting time on a non-working day of &lt; 8 h/day (10.1 ± 5.6% vs. 11.5 ± 5.0%; p = 0.01). After adjustment for confounding factors for vascular function, the odds of having the lowest tertile of FMD was significantly higher in subjects with sitting time on a non-working day of ≥6 h/day than in subjects with sitting time on a non-working day of &lt;6 h/day. The odds of having the lowest tertile of NID was significant higher in subjects with sitting time on a non-working day of ≥ 8 h/day than in subjects with sitting time on a non-working day of &lt; 8 h/day. These findings suggest that prolonged sitting time on a non-working day is associated with blunted FMD and blunted NID.

DOI： 10.1038/s41598-022-10242-8

PubMed

その他リンク： https://www.nature.com/articles/s41598-022-10242-8

記述言語：英語   出版者・発行元：SPRINGER  

Background The association between N-terminal pro-brain natriuretic peptide (NT-proBNP) and stroke in Japanese hemodialysis (HD) outpatients is unclear. Therefore, in this study, we investigate whether high NT-proBNP levels are associated with future stroke events in this population. Methods This was a multicenter prospective observational study with post hoc analysis. Baseline NT-proBNP levels were measured at the first HD session of the week and classified into tertiles (first tertile: < 2255 pg/mL; second tertile: >= 2255 and < 5657 pg/mL; third tertile: >= 5657 pg/mL). Overall hospitalization-free survival rates were compared using the Kaplan-Meier method. The association between NT-proBNP level and hospitalization for stroke was assessed using the multivariate Cox proportional hazards models. Results During a 5-year follow-up of 1,229 patients, 103 (8.4%) were hospitalized and 23 (1.9%) died from stroke. The hospitalization-free survival rate for ischemic stroke was lowest in the third tertile (P < 0.01). The crude hazard ratio (HR) of hospitalization was higher in the third tertile compared with the first tertile for both ischemic stroke (HR: 3.92; 95% confidence interval [CI] 2.08-7.37; P < 0.01) and hemorrhagic stroke (HR: 3.75; 95% CI 1.35-10.43; P = 0.01). On multivariate Cox hazard analysis, the adjusted HRs for ischemic stroke were higher in the third tertile. The hospitalization-free survival rates for hemorrhagic stroke and the adjusted HRs did not differ significantly. Conclusions Elevated NT-proBNP level was associated with hospitalization for ischemic stroke, suggesting that NT-proBNP level is a valid biomarker for predicting hospitalization for ischemic stroke in HD outpatients.

DOI： 10.1007/s10157-022-02254-5

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

Background and aims: Ankle-brachial index (ABI) has been used as a vascular marker of atherosclerosis for car-diovascular risk assessment. However, it is unclear whether there is a difference in cardiovascular risk between patients with low ABI (<1.00) in one leg (unilateral low ABI) and patients with low ABIs in both legs (bilateral low ABI). Therefore, we investigated the associations of cardiovascular disease (CVD) with unilateral low ABI and bilateral low ABI to determine whether cardiovascular risk is higher in patients with bilateral low ABI than in patients with unilateral low ABI.Methods: We measured ABI in 2226 subjects.Results: The prevalence of CVD was higher in patients with bilateral low ABI than in individuals with normal ABI (1.00-1.40) and patients with unilateral low ABI (49.2%, 25.7% and 17.0%, respectively; p < 0.001). Multi-variate analysis revealed that bilateral low ABI was significantly associated with an increased risk of CVD (OR, 2.30; 95% CI, 1.16 to 4.54; p = 0.02), whereas there was no significant association between unilateral low ABI and CVD (OR, 0.83; 95% CI, 0.47 to 1.46; p = 0.51). Propensity score matching analysis showed that the prevalence of CVD was significantly higher in patients with bilateral low ABI than in patients with unilateral low ABI (45.5% vs. 27.3%, p = 0.02).Conclusions: Cardiovascular risk may be higher in patients with bilateral low ABI than in patients with unilateral low ABI. More attention should be paid to whether a low ABI is present in one leg or in both legs for more precise cardiovascular risk assessment.

DOI： 10.1016/j.atherosclerosis.2022.09.012

PubMed

記述言語：英語   出版者・発行元：AMER PHYSIOLOGICAL SOC  

The transcription factors hypoxia-inducible factor-1 alpha and -2 alpha (HIF-1 alpha/2 alpha) are the major regulators of the cellular response to hypoxia and play a key role in renal fibrosis associated with acute and chronic kidney disease. Jumonji domain-containing 1a (JMJD1A), a histone H3 lysine 9 (H3K9) demethylase, is reported to be an important target gene of HIF-alpha. However, whether JMJD1A and H3K9 methylation status play a role in renal fibrosis is unclear. Here, we investigated the involvement of HIF-alpha, JMJD1A, and monomethylated/dimethylated H3K9 (H3K9me1/H3K9me2) levels in unilateral ureteral obstruction (UUO)-induced renal fibrosis in mice. Intraperitoneal administration of FG4592, an inhibitor of HIF-alpha prolyl hydroxylase, which controls HIF-alpha protein stability, significantly attenuated renal fibrosis on days 3 and 7 following UUO. FG4592 concomitantly increased JMJD1A expression, decreased H3K9me1/me2 levels, reduced profibrotic gene expression, and increased erythropoietin expression in renal tissues of UUO mice. The beneficial effects of FG4592 on renal fibrosis were inhibited by the administration of JMJD1A-specific siRNA to mice immediately following UUO. Incubation of normal rat kidney-49F and/or -52E cells with transforming growth factor-beta 1 (TGF-beta 1) in vitro resulted in upregulated expression of a-smooth muscle actin and H3K9me1/me2, and these effects were inhibited by cotreatment with FG4592. In contrast, FG4592 treatment further enhanced the TGF-beta 1-stimulated upregulation of JMJD1A but had no effect on TGF-beta 1-stimulated expression of the H3K9 methyltransferase euchromatic histone-lysine N-methyltransferase 2. Collectively, these findings establish a crucial role for the HIF-alpha 1/2-JMJD1A-H3K9me1/me2 regulatory axis in the therapeutic effect of FG4592 in renal fibrosis. NEW & NOTEWORTHY Using a mouse model of renal fibrosis and transforming growth factor-beta 1-stimulated rat cell lines, we show that treatment with FG4592, an inhibitor of hypoxia-inducible factor-1 alpha and -2 alpha (HIF-1 alpha/2 alpha) prolyl hydroxylase decreases renal fibrosis and concomitantly reduces methylated lysine 9 of histone H3 (H3K9) levels via upregulation of Jumonji domain-containing 1a (JMJD1A). The results identify a novel role for the HIF-1 alpha/2 alpha-JMJD1A-H3K9 regulatory axis in suppressing renal fibrosis.

DOI： 10.1152/ajprenal.00083.2022

記述言語：英語   掲載種別：（MISC）研究発表要旨（国際会議）   出版者・発行元：(一社)日本放射線影響学会  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI  

The ischemia-reperfusion injury (IRI) of rat kidneys is used as a model of acute kidney injury. Salt-sensitive hypertension occurs in rats after IRI, and the distal nephrons play important roles in the development of this condition. We investigated the role of the mineralocorticoid receptor (MR) in the progression of IRI-induced salt-sensitive hypertension in rats. Fourteen days after right-side nephrectomy, IRI was induced by clamping the left renal artery, with sham surgery performed as a control. IRI rats were provided with normal water or water with 1.0% NaCl (IRI/NaCl), or they were implanted with an osmotic mini-pump to infuse vehicle or aldosterone (IRI/Aldo). Esaxerenone, a non-steroidal MR blocker (MRB), was administered to IRI/NaCl and IRI/Aldo rats for 6 weeks. MR expression increased by day 7 post-IRI. Blood pressure and urinary protein excretion increased in IRI/NaCl and IRI/Aldo rats over the 6-week period, but these effects were negated by MRB administration. The MRB attenuated the expression of the gamma-epithelial sodium channel (ENaC) and renal damage. The ENaC inhibitor, amiloride, ameliorated hypertension and renal damage in IRI/NaCl and IRI/Aldo rats. Our findings thus showed that MR upregulation may play a pivotal role in ENaC-mediated sodium uptake in rats after IRI, resulting in the development of salt-sensitive hypertension in response to salt overload or the activation of the renin-angiotensin-aldosterone system.

DOI： 10.3390/ijms23147831

記述言語：英語   掲載種別：研究論文（学術雑誌）  

In medical and occupational settings, ionizing irradiation of the circulatory system occurs at various dose rates. We previously found sparing and enhancing dose protraction effects for aortic changes in wild-type mice at 6 months after starting irradiation with 5 Gy of photons. Here, we further analyzed changes at 12 months after stating irradiation. Irrespective of irradiation regimens, irradiation little affected left ventricular function, heart weight, and kidney weight. Irradiation caused structural disorganizations and intima-media thickening in the aorta, along with concurrent elevations of markers for proinflammation, macrophage, profibrosis, and fibrosis, and reductions in markers for vascular functionality and cell adhesion in the aortic endothelium. These changes were qualitatively similar but quantitatively less at 12 months than at 6 months. The magnitude of such changes at 12 months was not smaller in 25 fractions (Frs) but was smaller in 100 Frs and chronic exposure than acute exposure. The magnitude at 6 and 12 months was greater in 25 Frs, smaller in 100 Frs, and much smaller in chronic exposure than acute exposure. These findings suggest that dose protraction changes aortic damage, in a fashion that depends on post-irradiation time and is not a simple function of dose rate.

DOI： 10.3390/cancers14143319

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI  

We evaluated the relationship of daily coffee intake with endothelial function assessed by flow-mediated vasodilation and vascular smooth muscle function assessed by nitroglycerine-induced vasodilation in patients with hypertension. A total of 462 patients with hypertension were enrolled in this cross-sectional study. First, we divided the subjects into two groups based on information on daily coffee intake: no coffee group and coffee group. The median coffee intake was two cups per day in the coffee group. There were significant differences in both flow-mediated vasodilation (2.6 +/- 2.8% in the no coffee group vs. 3.3 +/- 2.9% in the coffee group, p = 0.04) and nitroglycerine-induced vasodilation (9.6 +/- 5.5% in the no coffee group vs. 11.3 +/- 5.4% in the coffee group, p = 0.02) between the two groups. After adjustment for confounding factors, the odds ratio for endothelial dysfunction (OR: 0.55, 95% CI: 0.32-0.95) and the odds ratio for vascular smooth muscle dysfunction (OR: 0.50, 95% CI: 0.28-0.89) were significantly lower in the coffee group than in the no coffee group. Next, we assessed the relationship of the amount of daily coffee intake with vascular function. Cubic spline curves revealed that patients with hypertension who drank half a cup to 2.5 cups of coffee per day had lower odds ratios for endothelial dysfunction assessed by flow-mediated vasodilation and vascular smooth muscle dysfunction assessed by nitroglycerine-induced vasodilation. Appropriate daily coffee intake might have beneficial effects on endothelial function and vascular smooth muscle function in patients with hypertension.

DOI： 10.3390/nu14132719

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Background A few previous clinical studies have shown that chloride (Cl) contributes to the progression and development of hypertension or proteinuria. Therefore, we aimed to determine whether hyperchloremia is associated with hypertension or proteinuria in patients with chronic kidney disease (CKD) and to define the relationships between the reduction in serum Cl concentration associated with CKD treatment and improvements in hypertension and/or proteinuria. Methods We performed a retrospective observational study of new or referred patients with CKD who had hyperchloremia, moderate proteinuria, renal dysfunction, and hypertension. Patients taking medication for metabolic acidosis or with a history of dialysis were excluded. The participants' systolic and diastolic blood pressure (BP), serum sodium (Na) and Cl concentrations, and urinary protein (UP) concentration were measured at baseline and after 1 month of CKD treatment. Results Fifty-one patients with CKD were included in the study. Their serum Cl concentration independently correlated with sBP and UP at baseline (P = 0.022 and P = 0.033, respectively). After 1 month's CKD treatment, their serum Na and Cl concentrations, sBP, and UP were significantly lower. The change in sBP during the month (Delta sBP) correlated with the change in serum Cl (Delta Cl) (P = 0.012) but not with the change in serum Na. Multivariate analysis showed that Delta sBP was independently associated with Delta Cl (P = 0.029). Conclusions Hyperchloremia is an independent predictor of hypertension and proteinuria for patients with CKD.

DOI： 10.1007/s10157-022-02229-6

PubMed

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Hindawi Limited  

DOI： 10.1155/2022/6795274

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41440-022-00854-y

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGERNATURE  

An inverse association between height and the risk of cardiovascular disease has been reported. The objective of this study was to examine the association between height and endothelial function assessed by flow-mediated vasodilation (FMD). We evaluated cross-sectional associations of height with FMD in 7682 Japanese men. All participants were divided into four groups based on height: <155.0 cm, 155.0-164.9 cm, 165.0-174.9 cm, and >= 175.0 cm. Subjects in a lower quartile of FMD were defined as subjects having low FMD values. Univariate regression analysis revealed that height was significantly correlated with FMD (r = 0.14, p < 0.001). FMD values were 4.6 +/- 3.1% in the <155.0 cm group, 5.2 +/- 3.1% in the 155.0-164.9 cm group, 5.7 +/- 3.1% in the 165.0-174.9 cm group and 6.1 +/- 3.2% in the >= 175.0 cm group. FMD significantly increased in relation to an increase in height. Multiple logistic regression analysis revealed that higher height groups were significantly associated with a decreased risk of low FMD value compared with the <155.0 cm group after adjustments for age, presence of hypertension, dyslipidemia, diabetes, current smoking, and brachial artery diameter. FMD was low in subjects with a short stature compared with that in subjects with tall stature. Individuals with a short stature may require intensive interventions to reduce the risk of cardiovascular events.

DOI： 10.1038/s41440-021-00785-0

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/jdi.13705

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-022-12205-5

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.5551/jat.63285

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Klotho is an antiaging protein reported to suppress transforming growth factor-I31 (TGF-I31) signaling. Aging kidneys are characterized by interstitial fibrosis, accumulation of cell cycle-arrested cells, and increased levels of oxidative stress. TGF-I31 signaling is involved in these processes. In this study, we investigated whether klotho overexpression improves these features in the kidneys of aging mice and examined the inhibitory effect of klotho on signaling molecules related to transforming growth of TGF-I31. Klotho transgenic (KLTG) and wild-type (WT) mice were used, and 8-wk-old and 24-mo-old mice were defined as young and aging, respectively. We found that klotho expression was decreased in aging WT mice, but it was maintained in aging KLTG mice. Klotho overexpression improved the survival of 24-mo-old mice. Although the serum Ca2 thorn level was significantly lower in aging KLTG mice than in aging WT mice, the serum phosphate level did not differ between these mice. Klotho overexpression attenuated the increases in blood pressure, serum blood urea nitrogen level, and serum creatinine level in aging mice. Interstitial fibrosis, accumulation of cell cycle-arrested cells, and oxidative stress did not differ between young KLTG and WT mice, but they were significantly suppressed in aging KLTG mice compared with aging WT mice. Furthermore, the expression of TGF-I31-related signaling molecules was increased in aging WT mice, whereas it was inhibited in aging KLTG mice. These data suggest that klotho overexpression protects against kidney aging along with suppression of TGF-I31 signaling pathways. NEW & NOTEWORTHY Klotho is considered as an antiaging protein, and its overexpression may be a candidate therapy for protection against kidney damage with advanced aging. Although multiple factors are involved in the aging process, we showed that klotho overexpression inhibited interstitial fibrosis, accumulation of cell cycle-arrested cells, and increased levels of oxidative stress in the kidneys of aging mice, suppressing transforming growth factor-I31-related signaling pathways. The present data showed that klotho overexpression protects against age-associated kidney damage.

DOI： 10.1152/ajprenal.00609.2020

PubMed

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BMC  

Background Mesenchymal stem cells (MSCs) provide potential treatments for peritoneal fibrosis. However, MSCs cultured in media containing serum bring risks of infection and other problems. In this study, we compared the effect of human MSCs in serum-free medium (SF-MSCs) on peritoneal fibrosis with that of MSCs cultured in medium containing 10% fetal bovine serum (10%MSCs). Methods Peritoneal fibrosis was induced by intraperitoneally injecting 0.1% chlorhexidine gluconate (CG). SF-MSCs or 10%MSCs were intraperitoneally administered 30 min after the CG injection. Ten days after the CG and MSC injections, we performed histological analyses and peritoneal equilibrium testing. In the in vitro experiments, we used transforming growth factor (TGF)-beta 1-stimulated human peritoneal mesothelial cells incubated in conditioned medium from MSCs to examine whether the SF-MSCs showed enhanced ability to produce antifibrotic humoral factors. Results Histological staining showed that the SF-MSCs significantly suppressed CG-induced cell accumulation and thickening compared with that of the 10%MSCs. Additionally, the SF-MSCs significantly inhibited mesenchymal cell expression, extracellular matrix protein deposition and inflammatory cell infiltration. Peritoneal equilibration testing showed that compared with administering 10%MSCs, administering SF-MSCs significantly reduced the functional impairments of the peritoneal membrane. The in vitro experiments showed that although the conditioned medium from MSCs suppressed TGF-beta 1 signaling, the suppression did not significantly differ between the SF-MSCs and 10%MSCs. Conclusions Serum-free culture conditions can enhance the antifibrotic abilities of MSCs by suppressing inflammation. Administering ex vivo expanded SF-MSCs may be a potential therapy for preventing peritoneal fibrotic progression.

DOI： 10.1186/s13287-021-02273-1

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ijcard.2021.12.056

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI  

The purpose of this study was to evaluate whether heart failure with mildly reduced ejection fraction (HFmrEF) is associated with vascular dysfunction and whether vascular function predicts future deterioration of LVEF in patients with HFmrEF. We evaluated endothelial function assessed by flow-mediated vasodilation (FMD) and vascular smooth muscle function assessed by nitroglycerine-induced vasodilation (NID) in 69 patients with HFmrEF and 426 patients without HF and evaluated the future deterioration of LVEF, defined as a decrease in LVEF to <40%, in 39 patients with HFmrEF for up to 3 years. Both FMD and NID were significantly lower in patients with HFmrEF than in patients without HF. We categorized patients into two groups based on low tertiles of NID: a low group (NID of <7.0%) and an intermediate and high group (NID of >= 7.0%). There were significant differences between the Kaplan-Meier curves for the deterioration of LVEF in the two groups (p < 0.01). Multivariate Cox proportional hazard analysis revealed that NID of <7.0% was an independent predictor of future deterioration of LVEF in patients with HFmrEF. Both endothelial function and vascular smooth muscle function are impaired in patients with HFmrEF compared with those in patients without HF. In addition, low NID of <7.0% predicts future deterioration of LVEF.

DOI： 10.3390/jcm10245980

PubMed

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s13287-021-02548-7

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI  

Mesenchymal stromal cells (MSCs) have the potential to differentiate into a variety of mature cell types and are a promising source of regenerative medicine. The success of regenerative medicine using MSCs strongly depends on their differentiation potential. In this study, we sought to identify marker genes for predicting the osteogenic differentiation potential by comparing ilium MSC and fibroblast samples. We measured the mRNA levels of 95 candidate genes in nine ilium MSC and four fibroblast samples before osteogenic induction, and compared them with alkaline phosphatase (ALP) activity as a marker of osteogenic differentiation after induction. We identified 17 genes whose mRNA expression levels positively correlated with ALP activity. The chondrogenic and adipogenic differentiation potentials of jaw MSCs are much lower than those of ilium MSCs, although the osteogenic differentiation potential of jaw MSCs is comparable with that of ilium MSCs. To select markers suitable for predicting the osteogenic differentiation potential, we compared the mRNA levels of the 17 genes in ilium MSCs with those in jaw MSCs. The levels of 7 out of the 17 genes were not substantially different between the jaw and ilium MSCs, while the remaining 10 genes were expressed at significantly lower levels in jaw MSCs than in ilium MSCs. The mRNA levels of the seven similarly expressed genes were also compared with those in fibroblasts, which have little or no osteogenic differentiation potential. Among the seven genes, the mRNA levels of IGF1 and SRGN in all MSCs examined were higher than those in any of the fibroblasts. These results suggest that measuring the mRNA levels of IGF1 and SRGN before osteogenic induction will provide useful information for selecting competent MSCs for regenerative medicine, although the effectiveness of the markers is needed to be confirmed using a large number of MSCs, which have various levels of osteogenic differentiation potential.

DOI： 10.3390/cimb43030150

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We measured upstroke time in 509 patients with diabetes who had a normal ankle-brachial index (ABI) (1.00 ≤ ABI ≤ 1.40) (443 men and 66 women; mean age: 67.6 ± 10.8 years). The prevalence of cardiovascular disease was significantly higher in patients with prolonged upstroke time at the ankle than in patients with normal upstroke time. The association between prolonged upstroke time and a higher risk of cardiovascular disease remained significant after adjusting for confounders.

DOI： 10.1016/j.jdiacomp.2021.108044

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI  

Simple Summary: The circulatory system receives ionizing radiation at various dose rates. Here, we analyzed changes in the circulatory system of wild-type mice at six months after starting acute, intermittent or continuous irradiation with 5 Gy of photons. Irradiation had little effect on left ventricular function, heart weight, and kidney weight. In the aorta, acute exposure caused structural disorganizations and detachment of the aortic endothelium and intima-media thickening. These morphological changes were concomitant with increases in markers for profibrosis, fibrosis, proinflammation, and macrophages, along with decreases in markers for cell adhesion and vascular functionality in the aortic endothelium. Compared with acute exposure, the magnitude of such aortic changes was overall greater in 25 fractions, smaller in 100 fractions, and much smaller in chronic exposure. These findings suggest that dose protraction alters aortic vascular damage, in a way that is not a simple function of dose rate.During medical (therapeutic or diagnostic) procedures or in other settings, the circulatory system receives ionizing radiation at various dose rates. Here, we analyzed prelesional changes in the circulatory system of wild-type mice at six months after starting acute, intermittent, or continuous irradiation with 5 Gy of photons. Independent of irradiation regimens, irradiation had little impact on left ventricular function, heart weight, and kidney weight. In the aorta, a single acute exposure delivered in 10 minutes led to structural disorganizations and detachment of the aortic endothelium, and intima-media thickening. These morphological changes were accompanied by increases in markers for profibrosis (TGF-beta 1), fibrosis (collagen fibers), proinflammation (TNF-a), and macrophages (F4/80 and CD68), with concurrent decreases in markers for cell adhesion (CD31 and VE-cadherin) and vascular functionality (eNOS) in the aortic endothelium. Compared with acute exposure, the magnitude of such aortic changes was overall greater when the same dose was delivered in 25 fractions spread over 6 weeks, smaller in 100 fractions over 5 months, and much smaller in chronic exposure over 5 months. These findings suggest that dose protraction alters vascular damage in the aorta, but in a way that is not a simple function of dose rate.

DOI： 10.3390/cancers13215344

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

Hypoxia is a common pathway to the progression of end-stage kidney disease. Retinoic acid-inducible gene I (RIG-I) encodes an RNA helicase that recognizes viruses including SARS-CoV2, which is responsible for the production of interferon (IFN)-alpha/beta to prevent the spread of viral infection. Recently, RIG-I activation was found under hypoxic conditions, and klotho deficiency was shown to intensify the activation of RIG-I in mouse brains. However, the roles of these functions in renal inflammation remain elusive. Here, for in vitro study, the expression of RIG-I and IFN-alpha/beta was examined in normal rat kidney (NRK)-52E cells incubated under hypoxic conditions (1% O-2). Next, siRNA targeting RIG-I or scramble siRNA was transfected into NRK52E cells to examine the expression of RIG-I and IFN-alpha/beta under hypoxic conditions. We also investigated the expression levels of RIG-I and IFN-alpha/beta in 33 human kidney biopsy samples diagnosed with IgA nephropathy. For in vivo study, we induced renal hypoxia by clamping the renal artery for 10 min in wild-type mice (WT mice) and Klotho-knockout mice (Kl(-/-) mice). Incubation under hypoxic conditions increased the expression of RIG-I and IFN-alpha/beta in NRK52E cells. Their upregulation was inhibited in NRK52E cells transfected with siRNA targeting RIG-I. In patients with IgA nephropathy, immunohistochemical staining of renal biopsy samples revealed that the expression of RIG-I was correlated with that of IFN-alpha/beta (r = 0.57, P<0.001, and r = 0.81, P<0.001, respectively). The expression levels of RIG-I and IFN-alpha/beta were upregulated in kidneys of hypoxic WT mice and further upregulation was observed in hypoxic Kl(-/-) mice. These findings suggest that hypoxia induces the expression of IFN-alpha/beta through the upregulation of RIG-I, and that klotho deficiency intensifies this hypoxia-induced expression in kidneys.

DOI： 10.1371/journal.pone.0258856

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGERNATURE  

We evaluated the relationship between daily stair climbing activity and vascular function as assessed by flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID). This study was a cross-sectional study. A total of 374 patients with hypertension were enrolled. The subjects were divided into three groups based on their daily stair climbing habit: no stairs group, climbing stairs to the 2nd-floor group, and climbing stairs to the >= 3rd-floor group. There was a significant difference in FMD between the >= 3rd-floor group and the other two groups (3.3 +/- 2.5% vs. 2.3 +/- 2.7% and 2.4 +/- 2.7%, p = 0.02, respectively). FMD values were similar in the no stairs group and the 2nd-floor group (p = 0.96). There was a significant difference in NID between the no stairs group and the other two groups (7.4 +/- 4.2% vs. 10.9 +/- 5.3% and 11.3 +/- 5.1%, p < 0.001, respectively). NID values were similar in the second-floor group and the >= 3rd-floor group (p = 0.86). These findings suggest that both endothelial function and vascular smooth muscle function are impaired in individuals who do not climb stairs and that endothelial function but not vascular smooth muscle function is impaired in individuals who climb stairs to the second floor compared with individuals who climb stairs to the >= 3rd floor. Stair climbing activity, a simple method for assessing daily physical activity, may reflect vascular function in patients with hypertension.

DOI： 10.1038/s41440-021-00697-z

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Mesenchymal stromal cells (MSCs) are a potential therapeutic tool for pulmonary fibrosis. However, ex vivo MSC expansion using serum poses risks of harmful immune responses or unknown pathogen infections in the recipients. Therefore, MSCs cultured in serum-free media (SF-MSCs) are ideal for clinical settings; however, their efficacy in pulmonary fibrosis is unknown. Here, we investigated the effects of SF-MSCs on bleomycin-induced pulmonary inflammation and fibrosis compared to those of MSCs cultured in serum-containing media (S-MSCs). METHODS: SF-MSCs and S-MSCs were characterized in vitro using RNA sequence analysis. The in vivo kinetics and efficacy of SF-MSC therapy were investigated using a murine model of bleomycin-induced pulmonary fibrosis. For normally distributed data, Student's t test and one-way repeated measures analysis of variance followed by post hoc Tukey's test were used for comparison between two groups and multiple groups, respectively. For non-normally distributed data, Kruskal-Wallis and Mann-Whitney U tests were used for comparison between groups, using e Bonferroni's correction for multiple comparisons. All tests were two-sided, and P < 0.05 was considered statistically significant. RESULTS: Serum-free media promoted human bone marrow-derived MSC expansion and improved lung engraftment of intravenously administered MSCs in recipient mice. SF-MSCs inhibited the reduction in serum transforming growth factor-β1 and the increase of interleukin-6 in both the serum and the bronchoalveolar lavage fluid during bleomycin-induced pulmonary fibrosis. SF-MSC administration increased the numbers of regulatory T cells (Tregs) in the blood and lungs more strongly than in S-MSC administration. Furthermore, SF-MSCs demonstrated enhanced antifibrotic effects on bleomycin-induced pulmonary fibrosis, which were diminished by antibody-mediated Treg depletion. CONCLUSIONS: SF-MSCs significantly suppressed BLM-induced pulmonary inflammation and fibrosis through enhanced induction of Tregs into the lungs and corrected the dysregulated cytokine balance. Therefore, SF-MSCs could be a useful tool for preventing pulmonary fibrosis progression without the demerits of serum use.

DOI： 10.1186/s13287-021-02574-5

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PORTFOLIO  

A body shape index (ABSI) was proposed for estimation of abdominal adiposity. ABSI has been reported to have associations with cardiovascular risk factors and cardiovascular events. However, there is no information on the association between ABSI and endothelial function. We examined cross-sectional associations of ABSI with endothelial function in 8823 subjects (6773 men and 2050 women). Subjects with a lower quartile of flow-mediated vasodilation (FMD) were defined as subjects having endothelial dysfunction. Pearson's correlation coefficient analysis revealed that ABSI was negatively correlated with FMD (men, r = -0.23, P = 0.003; women, r = -0.32, P < 0.001). The areas under the curves of ABSI and body mass index to predict endothelial dysfunction were 0.64 (95% confidence interval [CI] 0.62-0.65) and 0.58 (95% CI 0.57-0.60) in men, and 0.68 (95% CI 0.66-0.71) and 0.59 (95% CI 0.56-0.61) in women, respectively. The cutoff values of ABSI for predicting subjects with endothelial dysfunction were 0.0796 (sensitivity, 55.2%; specificity, 65.5%) in men and 0.0823 (sensitivity, 56.2%; specificity, 73.4%) in women. Multivariate analysis revealed that an ABSI value higher than the cutoff value remained an independent predictor of endothelial dysfunction in both sexes. The results of our study suggest that ABSI calculation should be performed for evaluation of risk of cardiovascular events in both men and women.

DOI： 10.1038/s41598-021-97325-0

PubMed

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI  

Background: Although malnutrition and bone fracture are both major complications in patients undergoing hemodialysis, their association has not been clarified. The aim of our study was to clarify the association between the geriatric nutritional risk index (GNRI), an indicator of nutritional status, and the incidence of bone fractures in patients undergoing hemodialysis. Methods: We included 1342 registered patients undergoing hemodialysis and performed a post hoc analysis. We divided patients into the high GNRI group (>= 92), considered to have a low risk of malnutrition, and the low GNRI group (<92), considered to have a high risk of malnutrition. Fracture-free survival in the low and high GNRI groups was evaluated by the Kaplan-Meier method. Cox proportional hazards models were used to identify the risk factors for fractures requiring hospitalization. All results were stratified by sex. Results: New bone fractures developed in 108 (8.0%) patients in 5 years of follow-up. Bone fractures occurred more frequently in the low GNRI group compared with the high GNRI group (HR: 3.51, 95% CI: 1.91-6.42, p < 0.01 in males; HR: 2.47, 95% CI: 1.52-4.03, p < 0.01 in females). A low GNRI was significantly associated with an increased incidence of bone fractures, even after adjustment for covariates. However, the serum levels of calcium, phosphate, parathyroid hormone, and alkaline phosphatase were not associated with the incidence of bone fractures. Conclusions: A low GNRI is an independent risk factor for bone fractures in patients undergoing hemodialysis. Early intervention for the low GNRI group may be important in preventing the occurrence of fractures.

DOI： 10.3390/nu13082847

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Background The association between N-terminal pro brain natriuretic peptide (NT-proBNP) level and long-term mortality in Japanese hemodialysis patients has not been fully assessed. Methods This prospective, multicenter study included 1428 hemodialysis outpatients. Baseline NT-proBNP levels were measured at the first hemodialysis session of the week and participants were followed for 5 years. The areas under the curve were calculated from receiver operating characteristic curves. Groups determined by quartiles of baseline NT-proBNP level were assessed by the Kaplan-Meier method and log-rank test. The association between NT-proBNP level and mortality was assessed using multivariate Cox proportional hazards models. Results During the 5-year follow-up, we observed 370 deaths and 256 censored cases. The areas under the curve of pre-hemodialysis NT-proBNP for all-cause mortality and cardiovascular disease mortality after 1 year were 0.75 and 0.78, respectively, and significantly greater than the areas under the curve at the 3- and 5-year follow-up. Cut-off values for all-cause mortality and cardiovascular disease mortality after 1 year were 4550 and 5467 ng/L, respectively (sensitivity: 82% and 81%; specificity: 59% and 64%). Kaplan-Meier survival analysis showed that the group with pre-hemodialysis NT-proBNP >= 8805 ng/L had increased all-cause mortality (P < 0.001) and cardiovascular disease mortality (P < 0.001). Finally, multivariate Cox analysis showed that NT-proBNP level was associated with all-cause mortality (P < 0.001) and cardiovascular disease mortality (P = 0.004) independently from other clinical parameters. Conclusion NT-proBNP is a useful marker to predict both all-cause and cardiovascular disease mortality in hemodialysis patients.

DOI： 10.1007/s10157-021-02073-0

PubMed

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI  

Mesenchymal stem cells (MSCs) are a potential therapeutic tool for preventing the progression of acute kidney injury (AKI) to chronic kidney disease (CKD). Herein, we investigated the localization and maintenance of engrafted human bone marrow-derived MSCs in rats subjected to a renal ischemia-reperfusion injury (IRI) and compared the effectiveness of two intravascular injection routes via the renal artery or inferior vena cava. Renal artery injection of MSCs was more effective than intravenous injection at reducing IRI-induced renal fibrosis. Additionally, MSCs injected through the renal artery persisted in injured kidneys for over 21 days, whereas MSCs injected through the inferior vena cava survived for less than 7 days. This difference may be attributed to the antifibrotic effects of MSCs. Interestingly, MSCs injected through the renal artery were localized primarily in glomeruli until day 3 post-IRI, and they decreased in number thereafter. In contrast, the number of MSCs localized in tubular walls, and the interstitium increased gradually until day 21 post-IRI. This localization change may be related to areas of damage caused by IRI because ischemia-induced AKI leads to tubular cell damage. Taken together, these findings suggest renal artery injection of MSCs may be useful for preventing the progression of AKI to CKD.

DOI： 10.3390/ijms22084178

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Bach1 is a known transcriptional repressor of the heme oxygenase-1 (HO-1) gene. The purpose of this study was to determine whether angiogenesis is accelerated by genetic ablation of Bach1 in a mouse ischemic hindlimb model. Hindlimb ischemia was surgically induced in wild-type (WT) mice, Bach1-deficient (Bach1(-/-)) mice, apolipoprotein E-deficient (ApoE(-/-)) mice, and Bach1/ApoE double-knockout (Bach1(-/-)/ApoE(- /-)) mice. Blood flow recovery after hindlimb ischemia showed significant improvement in Bach1(-/-) mice compared with that in WT mice. Bach1(-/-)/ApoE(-/-) mice showed significantly improved blood flow recovery compared with that in ApoE- /mice to the level of that in WT mice. Migration of endothelial cells in ApoE-/mice was significantly decreased compared with that in WT mice. Migration of endothelial cells significantly increased in Bach1(-/-)/ ApoE(-/-) mice compared with that in ApoE- /mice to the level of that in WT mice. The expression levels of HO-1, peroxisome proliferator-activated receptor gamma co-activator-1 alpha, angiopoietin 1, and fibroblast growth factor 2 in endothelial cells isolated from Bach1-/-/ApoE-/mice were significantly higher than those in ApoE(-/-) mice. Oxidative stress assessed by anti-acrolein antibody staining in ischemic tissues and urinary 8-isoPGF2 alpha excretion were significantly increased in ApoE(-/-) mice compared with those in WT and Bach1(-/-) mice. Oxidative stress was reduced in Bach1(-/-)/ApoE-/mice compared with that in ApoE(-/-) mice. These findings suggest that genetic ablation of Bach1 plays an important role in ischemia-induced angiogenesis under the condition of increased oxidative stress. Bach1 could be a potential therapeutic target to reduce oxidative stress and potentially improve angiogenesis for patients with peripheral arterial disease.

DOI： 10.1016/j.mvr.2020.104126

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The association of body weight with cardiovascular events is still controversial. We evaluated the relationship between body mass index (BMI) and endothelial function. METHODS: We measured flow-mediated vasodilation (FMD) and BMI in 7682 men. All participants were divided into four groups by BMI: underweight (<18.5 kg/m2), normal weight (18.5 to 24.9 kg/m2), overweight (25.0 to 29.9 kg/m2), and obesity (≥30.0 kg/m2). RESULTS: Multiple logistic regression analysis revealed that overweight (OR: 1.30, 95% CI: 1.14-1.47; P < 0.001) and obesity (OR: 1.40, 95% CI: 1.09-1.80; P = 0.009) were associated with an increased risk of a low quartile of FMD. In 5571 younger adults (<60 years), overweight (OR: 1.34, 95% CI: 1.16-1.55; P < 0.001) and obesity (OR: 1.37, 95% CI: 1.04-1.81; P = 0.03) were associated with an increased risk of a low quartile of FMD, and underweight (OR: 0.56, 95% CI: 0.35-0.89; P = 0.01) was associated with a reduced risk of a low quartile of FMD. In 2111 older adults (≥60 years), underweight (OR: 2.16, 95% CI: 1.22-3.80; P = 0.008) was associated with an increased risk of a low quartile of FMD, and overweight and obesity were not associated with a risk of a low quartile of FMD. CONCLUSIONS: In Asian men, endothelial function was impaired in the overweight and obesity groups compared with that in the normal weight group. The risk for endothelial dysfunction was higher in obese younger adults than in obese older adults. The association of BMI with endothelial function may be different in young and elderly men. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.umin.ac.jp (University Hospital Medical Information Network Clinical Trials Registry) (UMIN000012952).

DOI： 10.1016/j.ijcard.2020.09.029

PubMed

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE RESEARCH  

Mesenchymal stem cells (MSCs) administered for therapeutic purposes can be activated by interferon-gamma (IFN-gamma) secreted from natural killer cells in injured tissues and exert anti-inflammatory effects. These processes require a substantial period of time, leading to a delayed onset of MSCs' therapeutic effects. In this study, we investigated whether pretreatment with IFN-gamma could potentiate the anti-fibrotic ability of MSCs in rats with ischemia-reperfusion injury (IRI) and unilateral ureter obstruction. Administration of MSCs treated with IFN-gamma strongly reduced infiltration of inflammatory cells and ameliorated interstitial fibrosis compared with control MSCs without IFN-gamma treatment. In addition, conditioned medium obtained from IFN-gamma-treated MSCs decreased fibrotic changes in cultured cells induced by transforming growth factor-beta 1 more efficiently than that from control MSCs. Most notably, secretion of prostaglandin E2 from MSCs was significantly increased by treatment with IFN-gamma. Increased prostaglandin E2 in conditioned medium obtained from IFN-gamma-treated MSCs induced polarization of immunosuppressive CD163 and CD206-positive macrophages. In addition, knockdown of prostaglandin E synthase weakened the anti-fibrotic effects of MSCs treated with IFN-gamma in IRI rats, suggesting the involvement of prostaglandin E2 in the beneficial effects of IFN-gamma. Administration of MSCs treated with IFN-gamma might represent a promising therapy to prevent the progression of renal fibrosis.

DOI： 10.1038/s41598-020-79664-6

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-020-80012-x

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1136/bmjopen-2020-045415

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

BACKGROUND: Increased serum triglyceride levels are independently associated with endothelial dysfunction. However, there is little evidence to define normal levels of triglycerides and there is little information on endothelial function in subjects with extremely low levels of triglycerides. OBJECTIVE: The purpose of this study was to determine the relationship between triglycerides, especially low levels of triglycerides, and vascular function. METHODS: We measured flow-mediated vasodilation (FMD) in 7047 subjects and nitroglycerine-induced vasodilation (NID) in 1017 subjects. We divided the subjects into eight groups by triglyceride levels: <50 mg/dL, 50-69 mg/dL, 70-89 mg/dL, 90-109 mg/dL, 110-129 mg/dL, 130-149 mg/dL, 150-199 mg/dL, and =200 mg/dL. RESULTS: FMD was significantly higher in subjects with triglyceride levels of <50 mg/dL than in sub-jects with triglyceride levels of 50-69 mg/dL, 70-89 mg/dL, 90-109 mg/dL, 110-129 mg/dL, 130-149 mg/dL, 150-199 mg/dL, and =200 mg/dL (p=0.002, p <0.001, p <0.001, p <0.001, p <0.001, p <0.001, and p<0.001, respectively). Using triglyceride levels of >200 mg/dL as a reference, the odds ratios for a lower quartile of FMD were significantly lower in the <50 mg/dL group, 50-69 mg/dL group, 70-89 mg/dL group, and 90-109 mg/dL group after adjustment for age, gender and other cardiovascular risk factors. There was a slight negative correlation between NID and triglycerides (r=-0.074; p=0.019). However, there was no significant differences in NID among the eight groups. CONCLUSIONS: FMD values were highest in subjects with extremely low levels of triglycerides (<50 mg/dL). Lower triglyceride levels were associated with better endothelial function. (C) 2021 National Lipid Association. Published by Elsevier Inc.

DOI： 10.1016/j.jacl.2021.04.004

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0256504

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN ATHEROSCLEROSIS SOC  

Aims: Volume elastic modulus (VE), an index of arterial elasticity, and arterial diameter of the brachial artery can be automatically measured by a newly developed oscillometric device. We investigated the associations of VE with flow-mediated vasodilation (FMD), an index of endothelium-dependent vasodilation, nitroglycerine-induced vasodilation (NID), an index of endothelium-independent vasodilation, and intima-media thickness (IMT) of the brachial artery and association of oscillometrically measured brachial artery diameter with ultrasonographically measured brachial artery diameter in patients with cardiovascular risk factors. Methods: Oscillometric measurements of VE and brachial artery diameter and ultrasound measurements of brachial artery diameter, FMD, NID, and IMT of the brachial artery were performed in 50 patients with cardiovascular risk factors. Results: The mean values were 2.1 +/- 0.4 mmHg/% for VE, 0.31 +/- 0.05 mm for brachial IMT, 4.48 +/- 0.70 mm for oscillometric brachial artery diameter, and 4.30 +/- 0.55 mm for ultrasound brachial artery diameter. VE significantly correlated with brachial IMT (r= 0.51, P<0.001), whereas there was no significant correlation of VE with FMD (r= -0.08, P= 0.58) or NID (r= 0.07, P= 0.61). Multivariate analysis revealed that VE was significantly associated with brachial IMT (beta= 0.33, P= 0.04). Oscillometric brachial artery diameter significantly correlated with ultrasound brachial artery diameter (r= 0.79, P<0.001). The Bland-Altman plot showed good agreement between oscillometric brachial artery diameter and ultrasound brachial artery diameter (mean difference, -0.17 mm; limits of agreement, -1.03 mm to 0.69 mm). Conclusions: In patients with cardiovascular risk factors, VE may represent atherosclerotic structural alterations of the vascular wall but not vascular function. The accuracy of oscillometric measurement of brachial artery diameter is acceptable.

DOI： 10.5551/jat.59261

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

Light to moderate alcohol consumption has protective effects on all-cause death and coronary artery disease in women. It is thought that light to moderate alcohol consumption has a beneficial effect on vascular function in women. We measured flow-mediated vasodilation (FMD) in 702 women aged 17-86 years who provided information on alcohol consumption. We divided the subjects into four groups: non-drinkers (0 g/week), light drinkers (>0 to 140 g/week), moderate drinkers (>140 to 280 g/week) and heavy drinkers (>280 g/week). There was no significant difference in FMD among the four groups. Multivariate regression analysis revealed that alcohol consumption in non-drinkers and light drinkers was not an independent predictor of FMD (beta = -0.001, P = 0.98). We compared 50 moderate drinkers and 50 non-drinkers matched for age and medical histories and 22 heavy drinkers and 22 non-drinkers in matched pair analysis. There was no significant difference in FMD between moderate drinkers and non-drinkers (8.2 +/- 4.3% vs. 8.1 +/- 3.5, P = 0.91), while FMD in heavy drinkers was significantly lower than that in non-drinkers (5.9 +/- 2.5% vs. 8.9 +/- 3.5%, P = 0.002). These findings suggest that heavy alcohol consumption is associated with endothelial dysfunction but that light to moderate alcohol consumption is not associated with endothelial dysfunction in women.

DOI： 10.1371/journal.pone.0243216

PubMed

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

The estimated morbidity rate of chronic kidney disease is 8% to 16% worldwide, and many patients with chronic kidney disease eventually develop renal failure. Thus, the development of new therapeutic strategies for preventing renal failure is crucial. In this study, we assessed the effects of daily low-intensity pulsed ultrasound (LIPUS) therapy on experimental hypertensive nephropathy and diabetic nephropathy. Unilateral nephrectomy and subcutaneous infusion of angiotensin II via osmotic mini-pumps were used to induce hypertensive nephropathy in mice. Immunohistochemistry revealed that daily LIPUS treatment ameliorated renal fibrosis and infiltration of inflammatory cells induced by angiotensin II. A similar therapeutic effect was also observed in mice with angiotensin II-induced hypertensive nephropathy in which splenectomy was performed. In addition, LIPUS treatment significantly decreased systolic blood pressure after 21 days. Subsequently, db/db mice with unilateral nephrectomy developed proteinuria; daily LIPUS treatment significantly reduced proteinuria after 42 days. In addition, immunohistochemistry revealed that renal fibrosis was significantly ameliorated by LIPUS treatment. Finally, LIPUS stimulation suppressed TGF-beta 1 (transforming growth factor-beta 1)-induced phosphorylation of Smad2 and Smad3 in HK-2 (human proximal tubular cell line) cells. LIPUS treatment may be a useful therapy for preventing the progression of renal fibrosis in patients with chronic kidney disease.

DOI： 10.1161/HYPERTENSIONAHA.120.15237

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE RESEARCH  

Cell therapy using intramuscular injections of autologous bone-marrow mononuclear cells (BM-MNCs) improves clinical symptoms and can prevent limb amputation in atherosclerotic peripheral arterial disease (PAD) patients with critical limb ischemia (CLI). The purpose of this study was to evaluate the effects of the number of implanted BM-MNCs on clinical outcomes in atherosclerotic PAD patients with CLI who underwent cell therapy. This study was a retrospective observational study with median follow-up period of 13.5 years (range, 6.8-15.5 years) from BM-MNC implantation procedure. The mean number of implanted cells was 1.2 +/- 0.7x10(9) per limb. There was no significant difference in number of BM-MNCs implanted between the no major amputation group and major amputation group (1.1 +/- 0.7x10(9) vs. 1.5 +/- 0.8x10(9) per limb, P=0.138). There was also no significant difference in number of BM-MNCs implanted between the no death group and death group (1.5 +/- 0.9x10(9) vs. 1.8 +/- 0.8x10(9) per patient, P=0.404). Differences in the number of BM-MNCs (mean number, 1.2 +/- 0.7x10(9) per limb) for cell therapy did not alter the major amputation-free survival rate or mortality rate in atherosclerotic PAD patients with CLI. A large number of BM-MNCs will not improve limb salvage outcome or mortality.

DOI： 10.1038/s41598-020-76886-6

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ENDOCRINE SOC  

Context: It remains unclear whether adrenalectomy has more beneficial effects than treatment with a mineralocorticoid receptor antagonist on vascular function in patients with aldosterone-producing adenoma (APA). Objective: The aim of this study was to compare the effects of adrenalectomy and treatment with eplerenone on vascular function in patients with APA. Design, Setting, and Patients: Flow-mediated vasodilation (FMD), as an index of endothelium-dependent vasodilation, and nitroglycerine-induced vasodilation (NID), as an index of endothelium-independent vasodilation, were measured to assess vascular function before and after a 3-month treatment with eplerenone and at 3 months after adrenalectomy in 23 patients with APA. Results: Flow-mediated vasodilation and NID after adrenalectomy were significantly higher than those before treatment with eplerenone (5.4 +/- 2.6% vs 2.7 +/- 1.9% and 14.8 +/- 4.7% vs 9.6 +/- 4.6%, P < 0.01, respectively) and those after treatment with eplerenone (5.4 +/- 2.6% vs 3.1 +/- 2.3% and 14.8 +/- 4.7% vs 11.0 +/- 5.3%, P < 0.01 and P = 0.03, respectively), while treatment with eplerenone did not alter FMD and NID compared with those before treatment with eplerenone. After adrenalectomy, the increase in FMD and NID were significantly correlated with a decrease in plasma aldosterone concentration and a decrease in the aldosterone-renin ratio. There were no significant relationships between FMD and changes in other parameters or between NID and changes in other parameters. Conclusions: Adrenalectomy, but not treatment with eplerenone, improved vascular function in patients with APA. Adrenalectomy may be more effective than treatment with eplerenone for reducing the incidence of future cardiovascular events in patients with APA.

DOI： 10.1210/clinem/dgaa561

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI  

Simple Summary There has been renewed interest in radiation effects on the circulatory system. Here, we analyzed prelesional changes in the descending thoracic aorta of wild-type mice up to six months after a single acute exposure to 0 or 5 Gy of Cs-137 gamma-rays. We found that irradiation promoted structural disorganizations and detachment of the aortic endothelium, enhanced vascular permeability, and led to partial loss of the aortic endothelium, decreases in endothelial nitric oxide synthase, and adherens junction proteins in the aortic endothelium, and increases in inflammation and macrophage markers in the aorta. These findings suggest that irradiation causes vascular damage manifested as endothelial cell loss and increased vascular permeability, and that a decrease in adherens junction and an increase in inflammation lead to macrophage recruitment, which is thought to be involved in the early stage of atherosclerosis. There has been a recent upsurge of interest in the effects of ionizing radiation exposure on the circulatory system, because a mounting body of epidemiological evidence suggests that irradiation induces cardio- and cerebrovascular disease at a much lower dose and lower dose rate than previously considered. The goal of our project is to determine whether dose protraction alters radiation effects on the circulatory system in a mouse model. To this end, the use of wild-type mice is pivotal albeit without manifestation of vascular diseases, because disease models (e.g., apolipoprotein E-deficient mice) are prone to hormetic responses following protracted exposures. As such, here, we first set out to analyze prelesional changes in the descending thoracic aorta of wild-type mice up to six months after a single acute exposure to 0 or 5 Gy of Cs-137 gamma-rays. Scanning electron microscopy demonstrated that irradiation facilitated structural disorganizations and detachment of the aortic endothelium. The Miles assay with an albumin-binding dye Evans Blue revealed that irradiation enhanced vascular permeability. Immunofluorescence staining showed that irradiation led to partial loss of the aortic endothelium (evidenced by a lack of adhesion molecule CD31 and 4 ',6-diamidino-2-phenylindole (DAPI) signals), a decrease in endothelial nitric oxide synthase and adherens junction protein (vascular endothelial (VE)-cadherin) in the aortic endothelium, along with an increase in inflammation (tumor necrosis factor (TNF)-alpha) and macrophage (F4/80) markers in the aorta. These findings suggest that irradiation produces vascular damage manifested as endothelial cell loss and increased vascular permeability, and that the decreased adherens junction and the increased inflammation lead to macrophage recruitment implicated in the early stage of atherosclerosis.

DOI： 10.3390/cancers12103030

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1177/1129729820959934

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The usefulness of brachial-ankle pulse wave velocity (baPWV), an index of arterial stiffness, is not fully known for the management of treated hypertensive patients with a history of coronary artery disease (CAD) who have blood pressure less than 130/80 mmHg, a recommended blood pressure target in the updated major hypertension guidelines. We analyzed data for 447 treated hypertensive patients with CAD enrolled in FMD-J Study A for assessment of the predictive value of baPWV for future cardiovascular events. The primary outcome was a composite of coronary events, stroke, heart failure, and sudden death. During a median follow-up period of 47.6 months, the primary outcome occurred in 64 patients. Blood pressure less than 130/80 mmHg was significantly associated with a lower risk of the composite outcome independent of other cardiovascular risk factors in treated hypertensive patients with CAD (hazard ratio, 0.59; 95% confidence interval (CI), 0.35-0.99; P = 0.04). In treated hypertensive patients with CAD who had blood pressure less than 130/80 mmHg, baPWV above the cutoff value of 1731 cm/s, derived from receiver-operator characteristic curve analysis for the composite outcome was significantly associated with a higher risk of the composite outcome independent of conventional risk factors (hazard ratio, 2.83; 95% CI, 1.02-7.91; P = 0.04). baPWV was an independent predictor of cardiovascular events in treated hypertensive patients with CAD who had blood pressure less than 130/80 mmHg, for whom measurement of baPWV is recommended for cardiovascular risk assessment.

DOI： 10.1038/s41440-020-0420-6

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

High and low hematocrit (Hct) and hemoglobin (Hb) levels are associated with the risk of cardiovascular disease. The purpose of this study was to determine the relationships of Hct, Hb and red blood cells (RBCs) with vascular function and structure. We measured flow-mediated vasodilation (FMD), nitroglycerin-induced vasodilation (NID), brachial intima media thickness (IMT), and brachial-ankle pulse wave velocity (baPWV) in 807 men. The subjects were divided into six groups according to the levels of Hct, Hb and RBCs. NID was highest in the 46.0-48.9% Hct group among the six groups according to Hct levels. Brachial IMT was lowest in the 46.0-48.9% Hct group among the six groups. There were no significant differences in FMD and baPWV among the six groups. We used 46.0-48.9% Hct as a reference to define the lower tertile. The adjusted odds ratio of being in the low tertile of NID was significantly higher in the < 42.9% and >= 49.0% Hct groups. Adjusted odds ratio of being in the low tertile of brachial IMT was significantly lower in the < 39.9% Hct groups. Similar results were obtained for Hb and RBCs. Low and high levels of Hct, Hb and RBCs were associated with vascular smooth muscle dysfunction, and low Hct levels were associated with abnormal vascular structure. Increases in the levels of Hct, Hb and RBCs within normal ranges may have beneficial effects on the vasculature.

DOI： 10.1038/s41598-020-68319-1

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1253/circj.cj-20-0129

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

The percentage of people aged 80 years or older in Japan has been increasing. The purpose of this study was to investigate the association between vascular functions and aging in the elderly population and to clarify the characteristics of vascular functions in subjects aged 80 years or older. We measured flow-mediated vasodilation (FMD), nitroglycerine-induced vasodilation (NID), and brachial-ankle pulse wave velocity (baPWV) in 737 subjects aged 60 years or older who visited the outpatient clinic at Hiroshima University Hospital. FMD and NID were significantly lower in subjects aged 80 years or older than in subjects aged 60-69 years or in subjects aged 70-79 years (1.9 ± 2.0% vs. 2.9 ± 2.6% and 2.7 ± 2.6%, P = 0.008 and P = 0.03, respectively and 8.6 ± 5.1% vs. 12.1 ± 5.6% and 11.2 ± 5.5%, P < 0.001 and P < 0.001, respectively). baPWV was significantly higher in subjects aged 80 years or older than in subjects aged 60-69 years or in subjects aged 70-79 years (1978 ± 452 cm/s vs. 1724 ± 319 cm/s and 1811 ± 318 cm/s, P < 0.001 and P < 0.001, respectively). Age over 80 years was significantly associated with lower FMD (OR, 2.02; 95% CI, 1.19-3.42; P = 0.01), lower NID (OR, 3.62; 95% CI, 2.13-6.17; P < 0.001), and higher baPWV (OR, 3.48; 95% CI, 1.99-6.08; P < 0.001) after adjustment for other cardiovascular risk factors. Vascular functions, including endothelial function, vascular smooth muscle function, and arterial stiffness, were shown to be further impaired in subjects aged 80 years or older, suggesting that vascular functions continue to be impaired throughout life with aging.

DOI： 10.1038/s41440-020-0435-z

PubMed

その他リンク： http://www.nature.com/articles/s41440-020-0435-z

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s13287-020-01642-6

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1253/circj.cj-19-1041

PubMed

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s10157-019-01842-2

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Previously, we found that the basic helix-loop-helix transcriptional repressor DEC1 interacts with the PPAR gamma:RXR alpha heterodimer, a master transcription factor for adipogenesis and lipogenesis, to suppress transcription from PPAR gamma target genes (Noshiro et al., Genes to Cells, 2018, 23:658-669). Because the expression of PPAR gamma and several of its target genes exhibits circadian rhythmicity in white adipose tissue (WAT), we examined the expression profiles of PPAR gamma target genes in wild-type and Dec1(-/-) mice. We found that the expression of PPAR gamma target genes responsible for lipid metabolism, including the synthesis of triacylglycerol from free fatty acids (FFAs), lipid storage and the lipolysis of triacylglycerol to FFAs, oscillates in a circadian manner in WAT. Moreover, DEC1 deficiency led to a marked increase in the expression of these genes at night (Zeitgeber times 16 and 22), resulting in disruption of circadian rhythms. Serum FFA levels in wild-type mice also showed circadian oscillations, but these were disrupted by DEC1 deficiency, leading to reduced FFA levels. These results suggest that PPAR gamma:RXR alpha and DEC1 cooperatively generate the circadian expression of PPAR gamma target genes through PPAR-responsive elements in WAT.

DOI： 10.1111/gtc.12752

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background Diagnostic criteria of flow-mediated vasodilation (FMD), an index of endothelial function, and nitroglycerin-induced vasodilation (NID), an index of vascular smooth muscle function, of the brachial artery have not been established. The purpose of this study was to propose diagnostic criteria of FMD and NID for normal endothelial function and normal vascular smooth muscle function. Methods and Results We investigated the cutoff values of FMD and NID in subjects with (risk group) and those without cardiovascular risk factors or cardiovascular diseases (no-risk group) in 7277 Japanese subjects (mean age 51.4±10.8 years) from the Flow-Mediated Dilation Japan study and the Flow-Mediated Dilatation Japan Registry study for analysis of the cutoff value of FMD and in 1764 Japanese subjects (62.2±16.1 years) from the registry of Hiroshima University Hospital for analysis of the cutoff value of NID. Receiver-operator characteristic curve analysis of FMD to discriminate subjects in the no-risk group from patients in the risk group showed that the optimal cutoff value of FMD to diagnose subjects in the no-risk group was 7.1%. Receiver-operator characteristic curve analysis of NID to discriminate subjects in the no-risk group from patients in the risk group showed that the optimal cutoff value of NID to diagnose subjects in the no-risk group was 15.6%. Conclusions We propose that the cutoff value for normal endothelial function assessed by FMD of the brachial artery is 7.1% and that the cutoff value for normal vascular smooth muscle function assessed by NID of the brachial artery is 15.6% in Japanese subjects. Clinical Trial Registration www.umin.ac.jp Unique identifiers: UMIN000012950, UMIN000012951, UMIN000012952, and UMIN000003409.

DOI： 10.1161/JAHA.119.013915

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/jcm9123796

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BMJ PUBLISHING GROUP  

Introduction Diabetes mellitus is associated with endothelial dysfunction. However, there is little information on the relationships of fasting blood glucose (FBG), including high normal blood glucose and impaired fasting glucose (IFG) with endothelial function. The purpose of this study was to evaluate the relationship between FBG level and flow-mediated vasodilation (FMD) using a large sample size. Research design and methods This study was a cross-sectional study. We measured FMD in 7265 subjects at 31 general hospitals. The subjects were divided into four groups based on FBG levels: <100, 100-109, 110-125, and >= 126 mg/dL or known diabetes. The subjects were also divided into six groups based on FBG levels: <90, 90-94, 95-99, 100-109, 110-125, and >= 126 mg/dL or known diabetes. Results FMD decreased in relation to increase in FBG level. There was a significant difference in FMD between the FBG of <100 mg/dL group and the other three groups (6.7 +/- 3.1% vs 5.9 +/- 2.8%, 5.7 +/- 3.1%, and 5.1 +/- 2.6%, respectively; p<0.001). After adjustment for confounding factors, the odds of having the lowest quartile of FMD were significantly higher in the FBG of 95-99, 100-104, 105-109, 110-125, and >= 126 mg/dL or known diabetes groups than in the FBG of the <90 mg/dL group. Conclusions These findings suggest that FBG of 100-109 mg/dL and FBG of 110-125 mg/dL are similarly associated with endothelial dysfunction and that a pre-IFG state (FBG of 95-99 mg/dL) is also a risk for endothelial dysfunction compared with FBG of

DOI： 10.1136/bmjdrc-2020-001610

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1161/JAHA.120.017139

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BMJ PUBLISHING GROUP  

Objectives The purpose of this study was to evaluate the relationship between high-density lipoprotein cholesterol (HDL-C) levels and endothelial function in women. Design Cross-sectional study. Setting 22 university hospitals and affiliated clinics in Japan. Participants 1719 Japanese women aged 17-90 years who were not receiving lipid-lowering therapy. Measures We evaluated flow-mediated vasodilation (FMD) and serum levels of HDL-C. All participants were divided into four groups by HDL-C level: low HDL-C (<40 mg/dL), moderate HDL-C (40-59 mg/dL), high HDL-C (60-79 md/dL) and extremely high HDL-C (>= 80 mg/dL). Results Univariate regression analysis revealed a significant relationship between FMD and HDL-C (r=0.12, p<0.001). FMD values were significantly smaller in the low HDL-C group (5.2%+/- 3.8%) and moderate HDL-C group (5.2%+/- 3.8%) than in the extremely high HDL-C group (6.7%+/- 3.4%) (p=0.024 and p=0.003, respectively), while there was no significant difference in FMD between the high HDL-C group and the extremely high HDL-C group. Multiple logistic regression analysis did not show a significant association between HDL-C levels and FMD. Conclusions Endothelial function increased in relation to HDL-C levels. However, there was no association of HDL-C levels with endothelial function after adjustment of traditional cardiovascular risk factors in women.

DOI： 10.1136/bmjopen-2020-038121

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Critical limb ischemia (CLI) is associated with a high risk of limb amputation. It has been shown that cell therapy is safe and has beneficial effects on ischemic clinical symptoms in patients with CLI. The aim of this study was to further investigate the outcomes of intramuscular injection of autologous bone-marrow mononuclear cells (BM-MNCs) in a long-term follow-up period in atherosclerotic peripheral arterial disease (PAD) patients who have no optional therapy. This study was a retrospective and observational study that was carried out to evaluate long-term clinical outcomes in 42 lower limbs of 30 patients with atherosclerotic PAD who underwent BM-MNC implantation. The median follow-up period was 9.25 (range, 6-16) years. The overall amputation-free rates were 73.0% at 5 years after BM-MNC implantation and 70.4% at 10 years in patients with atherosclerotic PAD. The overall amputation-free rates at 5 years and at 10 years after implantation of BM-MNCs were significantly higher in atherosclerotic PAD patients than in internal controls and historical controls. There were no significant differences in amputation rates between the internal control group and historical control group

DOI： 10.1038/s41598-019-44176-5

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.kint.2019.06.021

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

Background Low-grade albuminuria has been considered a predictor of cardiovascular mortality. We investigated the relationship between high-normal albuminuria and subclinical atherosclerosis in non-diabetic men with estimated glomerular filtration rate (eGFR) >= 60 mL/min/1.73 m(2). Methods In this cross-sectional study, 1,756 men with eGFR >= 60 mL/min/1.73 m(2) and urine albumin-to-creatinine ratio (UACR) <30 mg/g, who attended general health checkups between April 2012 and March 2015, underwent blood sampling, urinalysis, and carotid ultrasonography. We excluded the subjects who were diabetic and/or received an anti-hypertensive drug. Carotid intima-media thickness (IMT) and the number of focal atheromatous plaques were used as indicators of subclinical atherosclerosis. Multiple linear regression analysis was performed to identify clinical factors associated with carotid IMT. Poisson regression analysis was used to assess the determinants of the carotid plaque number. Results Median UACR was 4.8 mg/g (interquartile range, 3.6-6.9 mg/g). Compared with subjects with low-normal UACR (<10.0 mg/g), subjects with high-normal UACR (10.0-29.8 mg/g) had greater IMT and higher carotid plaque number. High-normal UACR was independently associated with thickened IMT in the model adjusted for conventional cardiovascular disease risk factors. Moreover, participants with high-normal UACR were also more likely to be associated with increased plaque count (prevalence ratio: 1.06; 95% confidence interval: 1.01-1.14) after adjustment for conventional cardiovascular disease risk factors. Conclusions Our results indicate that high-normal albuminuria is associated with both carotid IMT and plaque formation in the non-diabetic male population with eGFR >= 60 mL/min/1.73 m(2).

DOI： 10.1371/journal.pone.0218290

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Hypertension is associated with vascular failure, such as increased arterial stiffness, endothelial dysfunction, and vascular smooth muscle dysfunction. The purpose of this study was to investigate the relationship between out-of-office blood pressure and vascular function in patients receiving antihypertensive drugs. We assessed out-of-office blood pressure, including daytime and night-time blood pressure, by home blood pressure monitoring and performed vascular function tests, including brachial-ankle pulse wave velocity (baPWV), flow-mediated vasodilation (FMD), and nitroglycerine-induced vasodilation (NID), in 169 patients receiving antihypertensive drugs, of whom 86 (50.9%) had normotension, 23 (13.6%) had isolated nocturnal hypertension (night-time systolic blood pressure ≥120 mm Hg), 26 (15.4%) had isolated daytime hypertension (daytime systolic blood pressure ≥135 mm Hg), and 34 (20.1%) had sustained hypertension (daytime and nocturnal hypertension). baPWV was significantly higher in patients with sustained hypertension than in those without sustained hypertension (1585 ± 257 cm/s in normotension; 1687 ± 267 cm/s in isolated nocturnal hypertension; 1688 ± 313 cm/s in isolated daytime hypertension; and 1923 ± 399 cm/s in sustained hypertension; P < 0.001). baPWV above the cutoff value of 1858 cm/s, derived from receiver operating characteristic curve analysis to diagnose patients with sustained hypertension, was significantly associated with sustained hypertension after adjustment of other confounding factors (odds ratio, 5.01; 95% confidence interval, 1.94-13.41; P < 0.001). In contrast, there was no significant association of home blood pressure status with FMD or NID in these patients. In patients receiving antihypertensive drugs, baPWV was significantly associated with sustained hypertension, whereas FMD and NID were impaired regardless of the home blood pressure status.

DOI： 10.1038/s41440-019-0240-8

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

The dipeptidyl peptidase-4 inhibitor saxagliptin is a widely used antihyperglycemic agent in patients with type 2 diabetes. The purpose of this study was to evaluate the effects of saxagliptin on endothelial function in patients with type 2 diabetes. This was a prospective, multicenter, interventional study. A total of 34 patients with type 2 diabetes were enrolled at four university hospitals in Japan. Treatment of patients was initially started with saxagliptin at a dose of 5 mg daily. Assessment of endothelial function assessed by flow-mediated vasodilation (FMD) and measurement of stromal cell-derived factor-1 alpha (SDF-1 alpha) were conducted at baseline and at 3 months after treatment with saxagliptin. A total of 31 patients with type 2 diabetes were included in the analysis. Saxagliptin significantly increased FMD from 3.1 +/- 3.1% to 4.2 +/- 2.4% (P = 0.032) and significantly decreased total cholesterol from 190 +/- 24 mg/dL to 181 +/- 25 mg/dL (P = 0.002), glucose from 160 +/- 53 mg/dL to 133 +/- 25 mg/dL (P &lt; 0.001), HbA1c from 7.5 +/- 0.6% to 7.0 +/- 0.6% (P &lt; 0.001), urine albumin-to-creatinine ratio from 63.8 +/- 134.2 mg/g to 40.9 +/- 83.0 mg/g (P = 0.043), and total

DOI： 10.1038/s41598-019-46726-3

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jacl.2019.06.004

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

KLOTHO deficiency is associated with the progression of kidney dysfunction, whereas its overexpression exerts renoprotective effects. Oxidative stress suppresses KLOTHO expression in renal epithelial cells but upregulates microRNA-200c (miR-200c) in human umbilical vein endothelial cells. In this study, we investigated whether oxidative stress-induced miR-200c is implicated in KLOTHO downregulation in human renal tubular epithelium (HK-2) cells. HK-2 cells were stimulated with hydrogen peroxide (H2O2) to examine the effect of oxidative stress. A luciferase reporter containing the KLOTHO 3'-UTR was used to investigate the effect of miR-200c on KLOTHO mRNA metabolism. The expressions of KLOTHO, oxidative stress markers, and miR-200c were determined in human kidney biopsy specimens. H2O2 suppressed KLOTHO expression without a reduction in KLOTHO mRNA levels but upregulated miR-200c expression. Similarly, transfection of a miR-200c mimic reduced KLOTHO levels and luciferase activity without a reduction in KLOTHO mRNA levels. In contrast, transfection of a miR-200c inhibitor maintained KLOTHO expression. Immunofluorescent assay revealed KLOTHO was present in the cytosol and nuclei of HK-2 cells. In human kidney biopsies, KLOTHO expression was inversely correlated with levels of oxidative stress markers (8-hydroxy-2'-deoxyguanosine: rho = -0.38, P = 0.026; 4-hydroxy-2-hexenal: rho = -0.35, P = 0.038) and miR-200c (rho = -0.34, P = 0.043). Oxidative stress-induced miR-200c binds to the KLOTHO mRNA 3'-UTR, resulting in reduced KLOTHO expression.

DOI： 10.1371/journal.pone.0218468

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

© American Journal of Hypertension, Ltd 2019. All rights reserved. For Permissions, please email: journals.permissions@oup.com. BACKGROUND: The effects of dipeptidyl peptidase 4 (DPP-4) inhibitors on blood pressure in patients with diabetes mellitus (DM) are controversial. There is no information on the effect of DPP-4 inhibitors on blood pressure and arterial stiffness in hypertensive patients with DM. We evaluated the effects of alogliptin on blood pressure and arterial stiffness in hypertensive patients with type 2 diabetes mellitus (T2DM). METHODS: Blood pressure and brachial-ankle pulse wave velocity (baPWV) were measured before and after 3, 6, and 12 months of treatment with alogliptin in 22 hypertensive patients with T2DM. RESULTS: After 3, 6, and 12 months, alogliptin treatment decreased hemoglobin A1c from 7.0 ± 0.97% to 6.4 ± 0.61%, 6.3 ± 0.58%, and 6.3 ± 0.75% (P &lt; 0.01, respectively), glucose from 8.6 ± 4.39 mmol/l to 7.05 ± 2.16, 7.05 ± 2.28, and 6.44 ± 1.50 mmol/l (P &lt; 0.01, respectively), systolic blood pressure from 137 ± 18 mm Hg to 127 ± 13, 125 ± 15, and 120 ± 17 mm Hg (P &lt; 0.01, respectively), diastolic blood pressure from 79 ± 13 mm Hg to 74 ± 8, 74 ± 10, and 70 ± 8 mm Hg (P &lt; 0.01, respectively) and baPWV from 1,947 ± 349 cm/second to 1,774 ± 259, 1,856 ± 361, and 1,756 ± 286 cm/second (P &lt; 0.01, respectively). A baseline baPWV value of 1,643 cm/second was the optimal cut-off value for patients who had reduced blood pressure after treatment with alogliptin (sensitivity of 83.3% and specificity of 75.0%). CONCLUSIONS: Alogliptin was associated with improvements not only in glucose metabolism but also in blood pressure and arterial stiffness in hypertensive patients with T2DM. The cut-off value of baPWV may enable identification of responders of decrease in blood pressure by alogliptin in hypertensive patients with T2DM. CLINICAL TRIALS REGISTRATION: Registration Number for Clinical Trial: UMIN000007722.

DOI： 10.1093/ajh/hpz065

Scopus

PubMed

記述言語：英語  

© American Journal of Hypertension, Ltd 2019. All rights reserved. For Permissions, please email: journals.permissions@oup.com. BACKGROUND: Differences between the effects of calcium channel blockers (CCBs) and other antihypertensive drugs on vascular function have not been fully investigated. The purpose of this study was to determine the confounding effect of CCBs on vascular function tests. METHODS: We measured flow-mediated vasodilation (FMD), nitroglycerine-induced vasodilation (NID), and brachial-ankle pulse wave velocity (baPWV) in 1,134 subjects who underwent health-screening examinations or who visited the outpatient clinic at Hiroshima University Hospital. RESULTS: FMD and NID were significantly lower (4.3 ± 3.2% vs. 2.3 ± 2.4% and 14.1 ± 5.8% vs. 10.6 ± 5.3%, P &lt; 0.001, respectively) and baPWV was significantly higher (1,604 ± 412 cm/s vs. 1,715 ± 343 cm/s, P &lt; 0.001) in subjects receiving CCB treatment than in subjects without CCB treatment. Multivariate analyses revealed that CCB treatment was significantly associated with lower FMD (β = -0.151, P &lt; 0.001) and lower NID (β = -0.120, P &lt; 0.001) but not with baPWV (β = 0.017, P = 0.42). Propensity score matching analyses revealed that FMD and NID were significantly lower and baseline brachial artery diameter was significantly larger in subjects receiving CCB monotherapy than in subjects without antihypertensive medication or subjects receiving non-CCB antihypertensive monotherapy. CONCLUSIONS: CCB treatment was significantly associated with lower FMD and lower NID, which might be, at least in part, due to larger baseline brachia artery diameter, whereas there was no significant association between CCB treatment and baPWV. FMD and NID may be of no use as prognostic markers of cardiovascular events in individuals who have been receiving CCB treatment. PUBLIC TRIALS REGISTRY NUMBER: Trial Number UMIN000003409.

DOI： 10.1093/ajh/hpz061

Scopus

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Objective: Primary aldosteronism is one of the most common cause of secondary hypertension. It is well known that the incidence of cardiovascular events is higher in patients with primary aldosteronism than in patients with essential hypertension. In a previous study, we showed that aldosterone-producing adenoma is associated with vascular function and structure. The aim of this study was to evaluate the effects of eplerenone on vascular function in the macrovasculature and microvasculature, arterial stiffness and Rho-associated kinase (ROCK) activity in patients with idiopathic hyperaldosteronism (IHA). Methods: Vascular function, including reactive hyperemia index (RHI), flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID), arterial stiffness including brachial-ankle pulse wave velocity (baPWV) and brachial intima-media thickness (IMT) and ROCK activity in peripheral leukocytes were measured before and after 12 weeks of treatment with eplerenone in 50 patients with IHA. Results: After 12 weeks, eplerenone decreased the aldosterone renin ratio but did not alter SBP and DBP. Eplerenone treatment increased log RHI from 0.56 +/- 0.25 to 0.69 +/- 0.25 (P &lt; 0.

DOI： 10.1097/hjh.0000000000001989

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPANESE CIRCULATION SOC  

BACKGROUND: Circulating triglyceride (TG) levels are a current focus as a residual risk for cardiovascular (CV) events. We evaluated the relationship between circulating TG levels and future CV events in patients with coronary artery disease (CAD) who were treated with conventional therapy. Methods and Results: We analyzed data for 652 patients who were enrolled in the FMD-J Study A. We investigated the associations between serum TG levels and first major CV events (death from CV cause, nonfatal acute coronary syndrome (ACS), nonfatal stroke, and CAD) for a 3-year follow-up period. Patients were divided into 4 groups based on serum TG level: low-normal (<100 mg/dL), high-normal (100-149 mg/dL), borderline hypertriglyceridemia (150-199 mg/dL), and moderate hypertriglyceridemia (≥200 mg/dL). During a median follow-up period of 46.6 months, 14 patients died (9 from CV causes), 16 had nonfatal ACS, 6 had nonfatal stroke, and 54 had CAD. The Kaplan-Meier curves for first major CV event among the 4 groups were significantly different (P=0.04). After adjustment for various confounders, serum TG level ≥100 mg/dL were significantly associated with an increased risk of first major CV events compared with serum TG level <100 mg/dL. CONCLUSIONS: Serum TG level may be a surrogate marker for predicting CV events in patients with CAD.

DOI： 10.1253/circj.CJ-18-1082

PubMed

記述言語：日本語   掲載種別：研究論文（研究会，シンポジウム資料等）   出版者・発行元：(一社)日本循環器学会  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Renal fibrosis is a histological manifestation that occurs in almost every type of chronic kidney disease. Histone variant H3.3 and its chaperone, histone cell cycle regulation defective homolog A (HIRA), serve as epigenetic marks that regulate transcriptional activity. In this study, we assessed the roles of histone H3.3 and HIRA in unilateral ureteral-obstruction (UUO) mice. In UUO mice, the levels of histone H3.3 and HIRA were significantly upregulated in the kidneys. These upregulated levels were decreased by a TGF-beta 1 neutralizing antibody. TGF-beta 1 induced histone H3.3 and HIRA expression in vitro via a Smad3-dependent pathway in normal rat kidney (NRK)-52E cells. Additionally, knockdown of HIRA expression decreased histone H3.3 expression and fibrogenesis in NRK-52E cells after TGF-beta 1 stimulation. Chromatin immunoprecipitation analysis revealed that promoters of fibrosis-related genes were immunoprecipitated with both histone H3.3 and HIRA in NRK-52E cells. Lastly, in human kidney biopsies from patients diagnosed with IgA nephropathy, histone H3.3 and HIRA immunostaining correlated positively with areas of fibrosis and estimated glomerular filtration rate. In conclusion, TGF-beta 1 induces expression of histone H3.3 and HIRA, which regulates expression of fibrosis-related genes.

DOI： 10.1038/s41598-018-32518-8

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：DUSTRI-VERLAG DR KARL FEISTLE  

Multicentric Castleman disease (MCD) is a rare systemic lymphopro-liferative disorder and is infrequently associated with renal complications that include amyloid A (AA) amyloidosis. Although it has been reported that patients with MCD and amyloidosis usually have a poor prognosis, recently, tocilizumab, a humanized antiinterleukin-6 receptor antibody, has emerged as an effective and specific treatment for AA amyloidosis secondary to chronic inflammatory disorders. Here we report a case of an MCD patient with secondary AA renal amyloidosis who was successfully treated with tocilizumab. The patient was initially referred to ncphrology specialists because of a decline in renal function and proteinuria. Percutaneous renal biopsy revealed the presence of Congo red-positive amorphous depositions and AA protein-positive areas in glotneruli, vessel walls, and interstitium, confirming a diagnosis of renal AA amyloidosis secondary to MCD. At 1 year after starting tocilizumab treatment, a second renal biopsy showed the clearance of amyloid deposits in the interstitium. These observations suggest that tocilizumab may be an effective therapy for AA amyloidosis secondaty to MCD.

DOI： 10.5414/CN109273

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

BACKGROUND: The usefulness of vascular function tests for management of patients with a history of coronary artery disease is not fully known. METHODS AND RESULTS: We measured flow-mediated vasodilation (FMD) and brachial-ankle pulse wave velocity (baPWV) in 462 patients with coronary artery disease for assessment of the predictive value of FMD and baPWV for future cardiovascular events in a prospective multicenter observational study. The first primary outcome was coronary events, and the second primary outcome was a composite of coronary events, stroke, heart failure, and sudden death. During a median follow-up period of 49.2 months, the first primary outcome occurred in 56 patients and the second primary outcome occurred in 66 patients. FMD above the cutoff value of 7.1%, derived from receiver-operator curve analyses for the first and second primary outcomes, was significantly associated with lower risk of the first (hazard ratio, 0.27; 95% confidence interval, 0.06-0.74; P=0.008) and second (hazard ratio, 0.32; 95% confidence interval, 0.09-0.79; P=0.01) primary outcomes. baPWV above the cutoff value of 1731 cm/s was significantly associated with higher risk of the first (hazard ratio, 1.86; 95% confidence interval, 1.01-3.44; P=0.04) and second (hazard ratio, 2.19; 95% confidence interval, 1.23-3.90; P=0.008) primary outcomes. Among 4 groups stratified according to the combination of cutoff values of FMD and baPWV, stepwise increases in the calculated risk ratio for the first and second primary outcomes were observed. CONCLUSIONS: In patients with coronary artery disease, both FMD and baPWV were significant predictors of cardiovascular events. The combination of FMD and baPWV provided further cardiovascular risk stratification. CLINICAL TRIAL REGISTRATION: URL: www.umin.ac.jp. Unique identifier: UMIN000012950.

DOI： 10.1161/JAHA.118.008588

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SAGE PUBLICATIONS LTD  

Purpose: This study was performed to investigate the effect of the balloon dilation pressure on the 12-month patency rate in patients with failed arteriovenous fistulas undergoing hemodialysis. Materials and methods: In this multicenter, prospective, randomized trial, the 4-mm-diameter YOROI balloon was used for dilation of stenotic lesions. The balloons were inflated to a pressure of 8atm (low-pressure group) or 30atm to achieve complete expansion (high-pressure group). The 12-month patency rate after balloon angioplasty was analyzed by the Kaplan-Meier method and log-rank test and/or a Cox proportional hazard model. We also investigated the dilation pressure required to achieve complete expansion in the high-pressure group. Results: In total, 71 patients were enrolled and allocated to either the low-pressure group (n=34) or the high-pressure group (n=37). The 12-month patency rates showed no significant difference between the low- and high-pressure groups (47% and 49%, respectively; p=0.87). In the low-pressure group, the patency rate was not different between patients with complete dilation and residual stenosis (44% and 50%, respectively; p=0.87). The Cox proportional hazard mo

DOI： 10.1177/1129729818760976

PubMed

記述言語：英語   出版者・発行元：SAGE PUBLICATIONS LTD  

Purpose: This study examined the clinical significance of N-terminal pro brain natriuretic peptide level as a cardiac marker in Japanese hemodialysis patients. Methods: This was a multicenter cross-sectional study involving 1428 Japanese hemodialysis patients. Ultrasonic cardiography data at post-hemodialysis were obtained from 395 patients. We examined whether serum N-terminal pro brain natriuretic peptide levels were associated with cardiac parameters and assessed cut-off values and investigated factors associated with a reduced ratio of N-terminal pro brain natriuretic peptide levels pre- and post-hemodialysis. Results: Multivariate logistic regression analysis showed that pre- and post-hemodialysis N-terminal pro brain natriuretic peptide levels were associated with left ventricular hypertrophy on electrocardiogram (odds ratio: 3.10; p<0.001 at pre-hemodialysis and odds ratio: 2.70; p<0.001 at post-hemodialysis) and left ventricular hypertrophy on ultrasonic cardiography (odds ratio: 3.06; p<0.001 at pre-hemodialysis and odds ratio: 3.15; p<0.001 at post-hemodialysis). Post-N-terminal pro brain natriuretic peptide levels were also significantly associated with ejection fraction on urine chorionic gonadotrophin (ultrasonic cardiography; odds ratio: 35.83; p<0.001). Receiver operating characteristic curves for predicting the presence of left ventricular hypertrophy on electrocardiogram and ultrasonic cardiography showed similar sensitivity (57.7%, 57.3% at pre-hemodialysis and 63.9%, 48.2% at post-hemodialysis) and specificity (66.5%, 72.9% at pre-hemodialysis and 59.2%, 81.9% at post-hemodialysis). Decreased ejection fraction on ultrasonic cardiography showed better sensitivity (78.6%) and specificity (88.7%). The N-terminal pro brain natriuretic peptide reduction ratio during a hemodialysis session correlated with Kt/V, membrane area, membrane type, modality, body weight gain ratio, treatment time, and ultrafiltration rate with multiple linear regression (R: 0.53; p<0.001 except for ultrafiltration rate (p=0.003)). Conclusion: Both pre- and post-hemodialysis N-terminal pro brain natriuretic peptide are associated with the presence of left ventricular hypertrophy in this population. The post-hemodialysis N-terminal pro brain natriuretic peptide level is a useful marker for systolic dysfunction.

DOI： 10.1177/0391398817752294

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Background The definition of sepsis was updated to sepsis-3 in February 2016. Currently, direct hemoperfusion therapy using the polymyxin B-immobilized fiber cartridge (PMX-DHP) is widely performed to treat sepsis and septic shock. However, the prognostic factors of PMX-DHPs in patients with sepsis using the new definition are unclear. We retrospectively assessed prognostic factors in patients who had received PMX-DHP therapy for sepsis and septic shock. Methods We included 71 patients with severe infection who underwent PMX-DHP treatment from January 2006 to August 2015 in this study. Participants were re-evaluated according to the criteria of sepsis-3. The patients were divided into two groups based on having survived (n = 59) or not survived (n = 12) for 28 days after PMX-DHP treatment. Clinical data before and after PMX-DHP treatment were compared between the two groups. Results Non-survivors showed a lower Glasgow Coma Scale (GCS) score before PMX-DHP treatment compared with 28-day survivors [12 (6-14) vs 14 (12-15), P &lt; 0.01]. Furthermore, pH after the first PMX-DHP session was significantly lower in non-survivors than in survivors (7.28 +/- 0.23 vs 7.39 +/- 0.06, P = 0.03).

DOI： 10.1007/s10157-018-1548-4

Scopus

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Dr. Dietrich Steinkopff Verlag GmbH and Co. KG  

Purpose: The purpose of this study was to evaluate acute effects of coffee with a high content of chlorogenic acids and different hydroxyhydroquinone contents on postprandial endothelial dysfunction. Methods: This was a single-blind, randomized, placebo-controlled, crossover-within-subject clinical trial. A total of 37 patients with borderline or stage 1 hypertension were randomized to two study groups. The participants consumed a test meal with a single intake of the test coffee. Subjects in the Study 1 group were randomized to single intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone or coffee with a high content of chlorogenic acids and a high content of hydroxyhydroquinone with crossover. Subjects in the Study 2 group were randomized to single intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone or placebo coffee with crossover. Endothelial function assessed by flow-mediated vasodilation and plasma concentration of 8-isoprostanes were measured at baseline and at 1 and 2 h after coffee intake. Results: Compared with baseline values, single intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone, but not coffee with a high content of chlorogenic acids and high content of hydroxyhydroquinone or placebo coffee, significantly improved postprandial flow-mediated vasodilation and decreased circulating 8-isoprostane levels. Conclusions: These findings suggest that a single intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone is effective for improving postprandial endothelial dysfunction. Clinical Trial Registration: URL for Clinical Trial: https://upload.umin.ac.jp
Registration Number for Clinical Trial: UMIN000013283.

DOI： 10.1007/s00394-018-1611-7

Scopus

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

Background. Spinal cord ischemia is a devastating complication after thoracic and thoracoabdominal aortic operations. In this study, we aimed to investigate the effects of mesenchymal stem cells (MSCs), which have regenerative capability and exert paracrine actions on damaged tissues, injected into rat models of spinal cord ischemia-reperfusion injury. Methods. Forty-five Sprague-Dawley rats were divided into sham, phosphate-buffered saline (PBS), and MSC groups. Spinal cord ischemia was induced in the latter two groups by balloon occlusion of the thoracic aorta. MSCs and PBS were then immediately injected into the left carotid artery of the MSC and PBS groups, respectively. Hindlimb motor function was evaluated at 6 and 24 hours. The spinal cord was removed at 24 hours after ischemia-reperfusion injury, and histologic and immunohistochemical analyses and real-time polymerase chain reaction assessments were performed. Results. Rats in the MSC and PBS groups showed flaccid paraparesis/paraplegia postoperatively. Hindlimb function was significantly better at 6 and 24 hours after ischemia-reperfusion injury in the MSC group than in the PBS group (p &lt; 0.05). The number of terminal deox

DOI： 10.1016/j.athoracsur.2017.12.014

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Background-Flow-mediated vasodilation (FMD) of the brachial artery has been used for the assessment of endothelial function. Considering the mechanism underlying the vasodilatory response of the brachial artery to reactive hyperemia, hyperemic shear stress (HSS), a stimulus for FMD; nitroglycerine-induced vasodilation (NID), an index of endothelium-independent vasodilation; and baseline brachial artery diameter (BAD) are also involved in vasodilatory response. The purpose of this study was to investigate the interrelationships among FMD, HSS, NID, baseline BAD, and cardiovascular risk factors. Methods and Results-We measured FMD, HSS, NID, and baseline BAD simultaneously in 1033 participants (633 men and 400 women; mean age: 58.6 +/- 17.0 years). Framingham risk score was negatively correlated with FMD, HSS, and NID and was positively correlated with baseline BAD. HSS and NID were positively correlated with FMD, and baseline BAD was negatively correlated with FMD. In participants with normal NID, FMD was correlated with HSS, NID, and baseline BAD, all of which were independent variables of FMD in multivariate analysis. In participants with impaired NID, FMD was correlated with NID

DOI： 10.1161/JAHA.117.006797

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

Transforming growth factor-beta 1 (TGF-beta 1) is a major mediator of peritoneal fibrosis and reportedly affects expression of the H3K4 methyltransferase, SET7/9. SET7/9-induced H3K4 mono-methylation (H3K4me1) critically activates transcription of fibrosis-related genes. In this study, we examined the effect of SET7/9 inhibition on peritoneal fibrosis in mice and in human peritoneal mesothelial cells (HPMCs). We also examined SET7/9 expression in nonadherent cells isolated from the effluent of peritoneal dialysis (PD) patients. Murine peritoneal fibrosis was induced by intraperitoneal injection of methylglyoxal (MGO) into male C57/BL6 mice over 21 days. Sinefungin, a SET7/9 inhibitor, was administered subcutaneously just before MGO injection (10 mg/kg). SET7/9 expression was elevated in both MGO-injected mice and nonadherent cells isolated from the effluent of PD patients. SET7/9 expression was positively correlated with dialysate/plasma ratio of creatinine in PD patients. Sinefungin was shown immunohistochemically to suppress expression of mesenchymal cells and collagen deposition, accompanied by decreased H3K4me1 levels. Peritoneal equilibration tests showed that sinefungin atten

DOI： 10.1371/journal.pone.0196844

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

High-normal albuminuria is an important risk factor for incident chronic kidney disease in diabetic populations, in contrast to an uncertain association in nondiabetic populations. This study aimed to reveal the relationship between high-normal albuminuria and incident chronic kidney disease in a Japanese nondiabetic population. A 10-year follow-up retrospective cohort study was performed involving 1378 Japanese men (mean age 44 +/- 5.3 years) without chronic kidney disease and diabetes mellitus. Chronic kidney disease was diagnosed as either estimated glomerular filtration rate &lt; 60 mL/min/1.73 m(2) or a urine albumin-to-creatinine ratio ae&lt;yen&gt; 30 mg/g. At baseline, age, estimated glomerular filtration rate, and the presence of hematuria, hypertension, and dyslipidemia were independently associated with the albumin-to-creatinine ratio. Among the 1378 participants, 185 (13.4%) fulfilled diagnostic criteria for chronic kidney disease over the 10-year follow-up period. Median annual estimated glomerular filtration rate decline showed a deterioration with increasing quartiles of baseline albumin-to-creatinine ratio (P = 0.004). Participants who had a baseline albumin-to-creatinine ra

DOI： 10.1007/s10157-017-1522-6

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

Background: Lower urinary tract symptoms (LUTS) is not only common symptoms in elderly men and women but also risk of future cardiovascular events. The purpose of this study was to evaluate the relationships of vascular function and structure with LUTS in men and women. Methods: We investigated flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID) as vascular function, brachial-ankle pulsewave velocity (baPWV) as vascular structure, and LUTS assessed by International Prostate Symptom Score (IPSS) in 287 men and 147 women. Results: IPSS was significantly correlated with traditional cardiovascular risk factors, Framingham risk score, FMD, NID and baPWV. Moderate to severe LUTS was associated with the prevalence of coronary heart disease in men but not in women. In men, FMD and NID were significantly lower in the moderate to severe LUTS group than in the none to mild LUTS group (2.1 +/- 2.0% vs. 4.0 +/- 3.0% and 9.3 +/- 6.1% vs. 12.8 +/- 6.6%, P &lt; 0.001, respectively). baPWV was significantly higher in the moderate to severe LUTS group than in the none to mild LUTS group (1722 +/- 386 cm/s vs. 1509 +/- 309 cm/s, P &lt; 0.001). In multivariate analysis, FMD was in

DOI： 10.1016/j.ijcard.2018.02.041

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

Deubiquitinating enzymes (DUBs) remove ubiquitin from their substrates and, together with ubiquitin ligases, play an important role in the regulation of protein expression. Although transforming growth factor (TGF)-beta 1-Smad signaling is a central pathway of renal fibrosis, the role of DUBs in the expression of TGF-beta receptors and Smads during the development of renal fibrosis remains unknown. In this study, we investigated whether PR-619, a pan-DUB inhibitor, suppresses fibrosis in mice with unilateral ureteral obstruction (UUO) and TGF-beta 1-stimulated normal rat kidney (NRK)-49F cells, a rat renal fibroblast cell line. Either the vehicle (dimethyl sulfoxide) or PR-619 (100 mu g) was intraperitoneally administered to mice after UUO induction once a day for 7 days. Administration of PR-619 attenuated renal fibrosis with downregulation of mesenchymal markers, extracellular matrix proteins, matrix metalloproteinases, apoptosis, macrophage infiltration, and the TGF-beta 1 mRNA level in UUO mice. Although type I TGF-beta receptor (TGF-beta RI), Smad2, Smad3, and Smad4 protein expression levels were markedly increased in mice with UUO, administration of PR-619 suppressed only Sma

DOI： 10.1371/journal.pone.0202409

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Obesity is a major public health problem in developed countries resulting from increased food intake and decreased energy consumption and usually associated with abnormal lipid metabolism. Here, we show that DEC1, a basic helix-loop-helix transcription factor, plays an important role in the regulation of lipid consumption in mouse brown adipose tissue (BAT), which is the major site of thermogenesis. Homozygous Dec1 deletion attenuated high-fat-diet-induced obesity, adipocyte hypertrophy, fat volume and hepatic steatosis. Furthermore, DEC1 deficiency increased body temperature during daytime and enhanced the expression of uncoupler protein 1, a key factor of thermogenesis, and various lipolysis-related genes in interscapular BAT. In vitro experiments suggested that DEC1 suppresses the expression of various lipolysis-related genes induced by the heterodimer of peroxisome proliferator-activated receptor gamma and retinoid X receptor alpha (RXR alpha ) through direct binding to RXRa. These observations suggest that enhanced lipolysis in BAT caused by DEC1 deficiency leads to an increase in lipid consumption, thereby decreasing lipid accumulation in adipose tissues and the liver. Thus,

DOI： 10.1111/gtc.12607

Web of Science

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Blood pressure shows a circadian rhythm, and recent studies have suggested the involvement of a molecular clock system in its control. In the clock system, the CLOCK (circadian locomotor output cycles kaput):BMAL1 (brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein-1) heterodimer enhances promoter activity of clock genes, and DEC1 (BHLHE40/STRA13/SHARP-2) represses CLOCK/BMAL1-enhanced promoter activity through competition for binding to the clock element, CACGTG E-box. However, the molecular mechanisms by which this system regulates blood pressure remain unclear. Here, we show that DEC1 suppressed the expression of ATP1B1, which encodes the 1 subunit of the Na+/K+-ATPase and elevated blood pressure. Using chromatin immunoprecipitation and chromatin immunoprecipitation-on-chip analyses, we found that DEC1 and CLOCK bound to E-boxes in the ATP1B1 promoter. Luciferase assays revealed that CLOCK:BMAL1 heterodimer enhanced transcription from the ATP1B1 promoter, whereas DEC1 suppressed this transactivation. Accordingly, Atp1b1 mRNA and protein levels in mouse kidney, aorta, and heart showed a circadian rhythm that was antiphasic to the blood pressure rhythm. F

DOI： 10.1161/HYPERTENSIONAHA.118.11075

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

Backgrounds: Nitroglycerine-induced vasodilation (NID) is usually assessed as a control test for flow-mediated vasodilation (FMD). However, NID per se is impaired in patients with high cardiovascular risk. The purpose of this study was to investigate the associations of chronic kidney disease (CKD) with NID and FMD. Methods: We measured NID and FMD in a total of 1567 adult subjects without end-stage renal disease (ESRD), 28% of whom had CKD as judged by measurements of estimated glomerular filtration rate (995 men and 572 women; mean age, 59.0 +/- 16.9 years; age range, 18 to 92 years). Results: NID was significantly smaller in patients with CKD than in those without CKD (10.8 +/- 6.0% vs. 12.7 +/- 5.7%, P &lt; 0.001). The prevalence of vascular smooth muscle dysfunction, defined as NID of less than the division point for the lowest quartile, was significantly higher in patients with CKD than in those without CKD (37.5% vs. 21.5%, P &lt; 0.001). Multivariate analysis revealed that CKD was independently associated with vascular smooth muscle dysfunction (OR: 1.36, 95% CI: 1.02 to 1.81, P = 0.04). FMD was significantly smaller in patients with CKD than in those without CKD (3.1 +/- 2.8% vs

DOI： 10.1016/j.ijcard.2017.10.122

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

Background and aims: Baseline brachial artery (BBA) diameter has been reported to be a potential confounding factor of flow-mediated vasodilation (FMD). The purpose of this study was to evaluate the relationships between BBA diameter and cardiovascular risk factors and compare the diagnostic accuracy of BBA diameter in subjects without cardiovascular risk factors and patients with cardiovascular disease (CVD) with that of FMD. Methods: We measured BBA diameter and FMD in 5695 male subjects. In addition, we retrospectively investigated the incidence of cardiovascular events using another population sample consisting of 440 male subjects, to compare the accuracy of BBA diameter with that of FMD in predicting cardiovascular events. Results: BBA diameter and FMD significantly correlated with age, body mass index, systolic blood pressure, diastolic blood pressure, triglycerides, high-density lipoprotein cholesterol, and glucose as well as Framingham risk score. The prevalence of cardiovascular risk factors and CVD increased with the increase in BBA diameter and FMD. Area under the curve (AUC) value of the receiver operating characteristic (ROC) curve for BBA diameter to diagnose subject

DOI： 10.1016/j.atherosclerosis.2017.11.022

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1177/0391398817752294

Web of Science

記述言語：日本語   掲載種別：（MISC）研究発表要旨（全国大会，その他学術会議）  

J-GLOBAL

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Serum used in culture medium brings risks of immune reactions or infections and thus may hinder using ex vivo expanded mesenchymal stem cells (MSCs) for medical treatment. Here, we cultured MSCs in a serum-free medium (SF-MSCs) and in a medium containing 10% fetal bovine serum (10%MSCs) and investigated their effects on inflammation and fibrosis. MSC-conditioned medium suppressed transforming growth factor-beta 1-induced phosphorylation of Smad2 in HK-2 cells, with no significant difference between the two MSCs. This finding suggests that the direct antifibrotic effect of SF-MSCs is similar to that of 10%MSCs. However, immunohistochemistry revealed that renal fibrosis induced by unilateral ureteral obstruction in rats was more significantly ameliorated by the administration of SF-MSCs than by that of 10%MSCs. Coculture of MSCs and monocytic THP-1 cell-derived macrophages using a Transwell system showed that SF-MSCs significantly induced polarization from the proinflammatory M1 to the immunosuppressive M2 phenotype macrophages, suggesting that SF-MSCs strongly suppress the persistence of inflammation. Furthermore, the gene expression of tumor necrosis factor-alpha-induced protein 6

DOI： 10.1002/sctm.17-0284

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

Background: Although reactive hyperemia-peripheral arterial tonometry (RH-PAT) is widely used for assessment of endothelial function, RH index (RHI) cannot be measured in some cases when pulse wave amplitude (PWA) is very low. Decrease in PWA is mainly caused by proper palmar digital artery (PPDA) stenosis. The purpose of this study was to evaluate the relationship between PWA measured by RH-PAT and stenosis of the PPDA measured by digital subtraction angiography and to evaluate the limitation of assessment of endothelial function measured by RHI in patients with PPDA stenosis. Methods: We measured baseline PWA in 51 fingers including the first to third fingers of both hands in 10 patients who had PPDA stenosis and in 66 fingers that were the first fingers of both hands in 33 subjects who had no PPDA stenosis. Severe stenosis was defined as over 75% by lower percent diameter stenosis between two PPDAs in a finger. Results: PWA was significantly correlated with stenosis of the digital artery (r=-0.55; P &lt; 0.0001). A PWV value of 300 mV was the optimal cut-off value for severe stenosis (sensitivity, 84.0%; specificity, 88.5%). Log RHI was significantly lower in patients with PPDA ste

DOI： 10.1016/j.ijcard.2017.10.069

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

Background: Measurement of flow-mediated vasodilation (FMD) is an established method for assessing endothelial function. Measurement of FMD is useful for showing the relationship between atherosclerosis and endothelial function, mechanisms of endothelial dysfunction, and clinical implications including effects of interventions and cardiovascular events. To shorten and simplify the measurement of FMD, we have developed a novel technique named short time FMD (stFMD). We investigated the validity of stFMD for assessment of endothelial function compared with conventional FMD. Methods and results: We evaluated stFMD and conventional FMD in 82 subjects including patients with atherosclerotic risk factors and cardiovascular disease (66 men and 16 women, 57 +/- 16 years). Both stFMD and conventional FMD were significantly correlated with age, systolic blood pressure, diastolic blood pressure and baseline brachial artery diameter. In addition, stFMD was significantly correlated with conventional FMD (r = 0.76, P &lt; 0.001). Bland-Altman plot analysis showed good agreement between stFMD and conventional FMD. Moreover, stFMD in the at risk group and that in the cardiovascular disease group were

DOI： 10.1016/j.ijcard.2018.05.006

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Recently, in addition to epithelial sodium channel alpha-subunit (alpha ENaC), the thiazide-sensitive sodium-chloride cotransporter (NCC) and pendrin, also known as sodium-independent chloride/iodide transporter, were reported to be activated by aldosterone. Here, we investigated whether chloride (Cl-) is responsible for hypertension, inflammation, and renal damage in aldosterone-infused rats. Following left nephrectomy, 8-wk-old male Sprague-Dawley rats were allocated into four groups: 1) drinking 1.0% sodium chloride solution with aldosterone infusion (Aldo/NaCl rats); 2) drinking 1.44% sodium bicarbonate solution with aldosterone infusion (Aldo/NaHCO3 rats); 3) drinking distilled water with aldosterone infusion (Aldo/water rats); and 4) drinking distilled water without aldosterone infusion (sham rats). Additionally, hemi-nephrectomized rats with aldosterone infusion were fed a 0.26% NaCl diet (control); 8.0% NaCl diet (high-Na/high-Cl); or a 4.0% NaCl 6.67% sodium citrate diet (high-Na/half-Cl). Last, Aldo/NaCl rats were treated with or without hydrochlorothiazide. Blood pressure in the Aldo/NaCl rats was significantly higher than in the Aldo/NaHCO3 rats, which was associated wi

DOI： 10.1152/ajprenal.00504.2016

Web of Science

記述言語：英語   掲載種別：（MISC）研究発表要旨（全国大会，その他学術会議）  

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Hypertension is associated with endothelial dysfunction. Blood pressure significantly correlates with endothelial function in antihypertensive drug-naive subjects. The purpose of this study was to determine whether treatment status affects the relationship between blood pressure and endothelial function. We measured flow-mediated vasodilation (FMD) in 2297 subjects, including 1822 antihypertensive drug-naive subjects and 475 treated hypertensive patients. FMD significantly decreased in relation to increase in systolic blood pressure (8.2 +/- 3.1% in subjects with systolic blood pressure of &lt;120 mm Hg, 7.5 +/- 2.8% for 120-129 mm Hg, 7.1 +/- 2.8% for 130-139 mm Hg, and 6.7 +/- 2.6% for &gt;= 140 mm Hg; P&lt;0.001). Systolic blood pressure was independently associated with FMD in untreated subjects. In contrast, there was no significant relationship between systolic blood pressure and FMD in treated hypertensive patients (4.6 +/- 3.1% in treated hypertensives with systolic blood pressure of &lt;120 mm Hg, 4.8 +/- 2.7% for 120-129 mm Hg, 4.9 +/- 2.8% for 130-139 mm Hg, and 4.5 +/- 2.3% for &gt;= 140 mm Hg; P=0.77). Propensity score matching analysis revealed that the prevalence of endothelial dysfunction defined as FMD of less than the division point for the lowest tertile, and the middle tertile of FMD was significantly higher in treated hypertensive patients than in untreated subjects in all systolic blood pressure categories. Endothelial function assessed by FMD was impaired regardless of the level of blood pressure achieved by antihypertensive drug treatment in hypertensive patients.

DOI： 10.1161/HYPERTENSIONAHA.117.09612

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Renal fibrosis is a common pathological feature of the progression of chronic kidney disease. Although valproic acid (VPA) has been recently shown to induce autophagy, the effect of VPA-induced autophagy on renal fibrosis remains unknown. We, therefore, investigated whether VPA-induced autophagy suppresses renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO).
Male C57BL/6 mice were divided into five groups (n = 8 per group): (1) sham group; (2) vehicle group; (3) VPA-treated group; (4) 3-methyladenine (3-MA; autophagy inhibitor)-treated group; and (5) VPA plus 3-MA-treated group. Mice underwent UUO and the kidneys were studied after 5 days. We also investigated the effect of VPA-induced autophagy on alpha-smooth muscle actin (alpha-SMA) in transforming growth factor (TGF)-beta 1-stimulated rat kidney fibroblasts and epithelial cells.
VPA attenuated renal fibrosis and induced autophagy in UUO mice, while 3-MA increased renal fibrosis and suppressed autophagy. In addition, the anti-fibrotic effect of VPA was diminished by 3-MA in UUO mice. In rat kidney fibroblasts and epithelial cells, VPA suppressed TGF-beta 1-stimulated alpha-SMA expression and induced autophagy. In contrast, 3-MA enhanced alpha-SMA expression while inhibiting autophagy. Furthermore, the combined use of VPA and 3-MA treatments increased the expression of alpha-SMA compared with VPA treatment alone in TGF-beta 1-stimulated rat kidney fibroblasts and epithelial cells, which was accompanied by the inhibition of autophagy.
These findings suggest that VPA may be a candidate drug for the treatment of renal fibrosis through the induction of autophagy.

DOI： 10.1007/s10157-016-1365-6

Web of Science

記述言語：日本語   掲載種別：（MISC）研究発表要旨（全国大会，その他学術会議）   出版者・発行元：(NPO)日本高血圧学会  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

Background: Periodontal disease is associated with endothelial dysfunction, leading to cardiovascular disease. The effect of detailed tooth brushing behavior, not only frequency but also duration of tooth brushing, on endothelial function is unclear. The purpose of this study was to evaluate the relationships of detailed methods of tooth brushing with vascular function.
Methods: We evaluated flow-mediated vasodilation (FMD), nitroglycerine-induced vasodilation, and frequency and duration of tooth brushing in 896 subjects. We divided the subjects into three groups according to the frequency and duration of tooth brushing: low frequency and short duration group (&lt; twice/day and &lt; 2 min/procedure), low frequency or short duration group (btwice/day or &lt; 2 min/procedure), non-low frequency and non-short duration group (&gt;= twice/day and &gt;= 2 min/procedure).
Results: FMD in the low frequency and short duration group was significantly lower than FMD in the low frequency or short duration group and FMD in the non-low frequency and non-short duration group [3.1 (2.7)% vs. 4.2 (3.1)% and 4.7 (3.1)%, P = 0.001 and &lt; 0.001, respectively]. Nitroglycerine-induced vasodilation was similar in the three groups. Using the non-low frequency and non-short duration group as the reference, the low frequency and short duration of tooth brushing group was significantly associated with an increased odds ratio of a low FMD tertile after adjustment for conventional risk factors (OR: 2.25, 95% CI: 1.39-3.59; P &lt; 0.001).
Conclusions: These findings suggest that low frequency and short duration of tooth brushing are associated with endothelial dysfunction. (C) 2017 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ijcard.2017.03.049

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

We investigated (1) the relationship between low-density lipoprotein cholesterol (LDL-C) and vascular function in patients receiving and those not receiving statin therapy and (2) optimal level of LDL-C for maintenance of vascular function. Flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID) were inversely correlated with LDL-C in the 957 statin naive subjects but not in the 392 subjects receiving statin therapy. In statin naive subjects, non-high LDL-C (&lt;= 100 mg/dL) was independently associated with a decrease in adjusted odds ratio of the low tertile of FMD (OR: 0.62, 95% CI: 0.45-0.85; P = 0.003) and NID (OR: 0.69, 95% CI: 0.50-0.96; P = 0.03). Adjusted odds ratio of the low tertile of FMD was significantly lower in the low LDL-C group (&lt;= 70 mg/dL) (OR: 0.47, 95% CI, 0.27-0.81; P = 0.006) and in the moderate LDL-C group (70.1-100 mg/dL) (OR: 0.66, 95% CI, 0.48-0.94; P = 0.02) than in the high LDL-C group (&gt;100 mg/dL). There was no significant difference in FMD between the low LDL-C group and moderate LDL-C group. There were significant relationships of FMD and NID with LDL-C levels in statin naive subjects. In a general population, LDL-C of = 100 mg/dL may be the optimal target level for maintenance of endothelial function.

DOI： 10.1038/s41598-017-09043-1

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPANESE CIRCULATION SOC  

Background: Osteoporosis and cardiovascular disease are major public health problems. A number of clinical studies have shown a link between osteoporosis and cardiovascular disease, but there is no information on the associations of risk of osteoporotic fracture with vascular function and vascular structure.
Methods and Results: The risk of major osteoporotic fracture was calculated using the World Health Organization fracture risk assessment tool (FRAX); vascular function was assessed using flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID), and vascular structure was assessed on brachial artery intima-media thickness (IMT) in 414 subjects (241 men and 173 women) who underwent health examinations. On univariate regression, FRAX was negatively correlated with FMD (total, r=-0.16, P&lt;0.001; men, r=-0.19, P=0.003; women, r=-0.25, P&lt;0.001) and NID (total, r=-0.22, P&lt;0.001; men, r=- 0.19, P=0.003; women, r=-0.30, P&lt;0.001) and was positively correlated with brachial artery IMT (total, r=0.12, P=0.02; men, r=0.22, P&lt;0.001; women, r=0.33, P&lt;0.001). On multivariate analysis FRAX remained an independent predictor of FMD, NID, and brachial artery IMT in both men and women.
Conclusions: Increase in the risk of osteoporotic fracture evaluated on FRAX is associated with vascular dysfunction and abnormal vascular structure in both men and women. Osteoporosis should be monitored in order to reduce the risk of cardiovascular events.

DOI： 10.1253/circj.CJ-16-1236

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC  

The presence of an earlobe crease (ELC) may be a simple sign to predict atherosclerosis. We evaluated the relation between ELC and vascular function. We measured flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID) and observed bilateral earlobes in 400 consecutive subjects. At first, the subjects were divided into 3 groups: non-ELC group, unilateral ELC group, and bilateral ELC group. FMD and NID were significantly lower in the unilateral and bilateral ELC groups than those in the non-ELC group. After adjustment of cardiovascular risk factors, bilateral ELC, but not unilateral ELC, was associated with lower FMD and lower NID. We also investigated whether an increase in the number of ELCs worsens endothelial function, whether the difference in ELC structure (cross stripes and/or ramification) affects endothelial function, and whether endothelial function is impaired in subjects with superficial wrinkles depending on age. The number of ELCs, shape of the ELC, and superficial wrinkles were not associated with endothelial dysfunction. In conclusion, these findings suggest that the presence of bilateral ELCs is associated with vascular dysfunction. (C) 2017 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.amjcard.2017.03.029

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

DOI： 10.1371/journal.pone.0173706

Scopus

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

Background: Endothelial dysfunction and abnormal vascular structure may be involved in the pathogenesis of chronic heart failure (HF). The purpose of this study was to evaluate simultaneously vascular function and vascular structure in patients with heart failure with preserved ejection fraction (HFpEF).
Methods: We measured flow-mediated vasodilatation (FMD) and nitroglycerine-induced vasodilation as indices of vascular function and intima-media thickness (IMT) as an index of vascular structure of the brachial artery in 41 patients with HFpEF (23 men and 18 women; mean age, 66 +/- 12 yr) and 165 patients without HF (95 men and 70 women; mean age, 54 +/- 16 yr).
Results: FMD was significantly smaller in patients with HFpEF than in patients without HF (2.9 +/- 2.1% versus 4.6 +/- 2.7%, P = 0.0002). Nitroglycerine-induced vasodilation was significantly smaller in patients with HFpEF than in patients without HF (9.3 +/- 4.1% versus 12.9 +/- 4.9%, P &lt; 0.0001). Brachial artery IMT was significantly larger in patients with HFpEF than in patients without HF (0.35 +/- 0.06 mm versus 0.31 +/- 0.07 mm, P = 0.0002). After adjustment for age, sex, hypertension, dyslipidemia, and diabetes mellitus, the associations remained significant between HFpEF and FMD (odds ratio, 0.79; 95% confidence interval, 0.66-0.92; P = 0.0032), nitroglycerine-induced vasodilation (odds ratio, 0.88; 95% confidence interval, 0.80-0.96; P = 0.0039), and brachial artery IMT (odds ratio, 1.08; 95% confidence interval, 1.01-1.17; P = 0.033).
Conclusions: These findings suggest that both endothelial dysfunction and abnormal vascular structure may contribute to the pathogenesis and maintenance of HFpEF. Endothelial function and vascular structure may be potential therapeutic targets for HFpEF. (C) 2017 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ijcard.2017.01.024

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

Background: Heavy drinking should be a predictor of endothelial dysfunction. However, there is little information on the effects of light to moderate alcohol consumption on endothelial function. The purpose of this study was to estimate the effects of dose-dependent alcohol consumption on endothelial function.
Methods: We measured flow-mediated vasodilation (FMD) in 2734 men aged 21-81 years who provided information on alcohol intake at 3 general hospitals. The subjects were divided into 5 groups; non-drinkers (0 g/week), light drinkers (&gt;0 to 140 g/week), moderate drinkers (&gt;140 to 280 g/week), heavy drinkers (&gt;280 to 420 g/week), and excessive heavy drinkers (&gt;420 g/week).
Results: FMD showed a gradual decrease in accordance with alcohol consumption in the entire study population (non-drinkers, 6.6 +/- 3.4%; light drinkers, 6.2 +/- 3.0%; moderate drinkers, 6.0 +/- 3.0%; heavy drinkers, 5.5 +/- 2.9%; excessive heavy drinkers, 5.3 +/- 3.0%; P &lt; 0.001). There was a significant difference in FMD between the light alcohol drinker group and the non-drinker group (P = 0.015). After adjustment for other risk factors, the odds of having FMD in the lowest quartile was found to be significantly increased in the 4 drinker groups than in the nondrinker group: light (OR, 1.38; 95% CI, 1.10 to 1.75), moderate (OR, 1.36; 95% CI, 1.01 to 1.82), heavy (OR, 2.05; 95% CI, 1.46 to 2.87), excessive (OR, 2.04; 95% CI, 1.43 to 2.89).
Conclusion: These findings suggest that FMD is impaired in relation to alcohol consumption and that FMD is significantly smaller even in light alcohol drinkers than in non-drinkers. Alcohol intake per se may be harmful for vascular function. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.ijcard.2016.12.065

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Background-A new device for automatic measurement of flow-mediated vasodilation (FMD) using an oscillometric method has been developed to solve technical problems of conventional FMD measurement. This device measures enclosed zone FMD (ezFMD). The purpose of this study was to evaluate the prognostic value of endothelial function assessed by ezFMD for future cardiovascular events.
Methods and Results-We measured ezFMD in 272 participants who underwent health-screening examinations. First, we investigated cross-sectional associations between ezFMD and cardiovascular risk factors, and then we assessed the associations between ezFMD and first major cardiovascular events (death from cardiovascular causes, stroke, and coronary revascularization). Univariate regression analysis revealed that ezFMD was significantly correlated with age, triglycerides, glucose, smoking packyears, estimated glomerular filtration rate, high-sensitivity C-reactive protein, and Framingham risk score. During a median followup period of 36.1 months (interquartile range 18.8-40.1 months), 12 participants died (6 from cardiovascular causes), 3 had stroke, 8 had coronary revascularization, and 10 were hospitalized for heart failure. There was no episode of acute coronary syndrome during the study period. Participants were divided into tertiles (low, intermediate, and high) based on ezFMD. Kaplan-Meier curves for first major cardiovascular events among the 3 groups were significantly different (P=0.004). After adjustment for cardiovascular risk factors, the low group was significantly associated with an increased risk of first major cardiovascular events compared with the high group (hazard ratio 6.47; 95% CI 1.09-125.55; P=0.038).
Conclusions-These findings suggest that endothelial function assessed by ezFMD may be useful as a surrogate marker of future cardiovascular events.

DOI： 10.1161/JAHA.116.004385

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

Background: Pigment epithelium-derived factor (PEDF) is a glycoprotein that belongs to the superfamily of serine protease inhibitors. It is thought that PEDF plays a protective role against atherosclerosis. Clinical studies have shown that serum levels of PEDF are increased in subjects with cardiovascular risk factors. The role of PEDF in cardiovascular disease is still controversial. The purpose of this study was to evaluate the associations between serum levels of PEDF and vascular function and structure.
Methods: We measured serum levels of PEDF, assessed vascular function by measurements of flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation in the brachial artery, and measured brachial artery intima-media thickness (IMT) in 150 subjects who underwent health examinations.
Results and conclusions: Univariate regression analysis revealed that serum level of PEDF was significantly correlated with body mass index, high-density lipoprotein cholesterol, glucose, FMD, nitroglycerine-induced vasodilation, and brachial artery IMT. Multivariate analysis revealed that serum levels of PEDF remained an independent predictor of nitroglycerine-induced vasodilation (beta = -0.20, P = 0.02) and brachial artery IMT (beta = 0.14, P = 0.03) after adjustment of cardiovascular risk factors, while serum level of PEDF was not associated with FMD (beta = -0.02, P = 0.79). These findings suggest that PEDF may be a factor directly associated with atherosclerosis. The serum level of PEDF may be a new biochemical marker of atherosclerosis. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.ijcard.2016.09.123

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：（MISC）研究発表要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

Background: Nitroglycerine-induced vasodilation, an index of endothelium-independent vasodilation, is measured for the assessment of vascular smooth muscle cell function or alterations of vascular structure. Both coronary and brachial artery responses to nitroglycerine have been demonstrated to be independent prognostic markers of cardiovascular events. The purpose of this study was to evaluate the nitroglycerine-induced vasodilation in coronary and brachial arteries in the same patients.
Methods: We measured nitroglycerine-induced vasodilation in coronary and brachial arteries in 30 subjects with suspected coronary artery disease who underwent coronary angiography (19 men and 11 women; mean age, 69.0 +/- 8.8 years; age range, 42-85 years).
Results and conclusions: The mean values of nitroglycerine-induced vasodilation in the brachial artery, left anterior descending coronary artery, and left circumflex coronary artery were 12.6 +/- 5.2%, 11.6 +/- 10.3%, and 11.9 +/- 11.0%, respectively. Nitroglycerine-induced vasodilation in the brachial artery correlated significantly with that in the left anterior descending coronary artery (r = 0.43, P = 0.02) and that in the left circumflex coronary artery (r = 0.49, P = 0.006). There was also a significant correlation between nitroglycerine-induced vasodilation in the left anterior descending coronary artery and that in the left circumflex coronary artery (r = 0.72, P &lt; 0.001). These findings suggest that vascular smooth muscle cell dysfunction is a systemic disorder and thus impairment of endothelium-independent vasodilation in peripheral arteries and that in coronary arteries are simultaneously present. Nitroglycerine-induced vasodilation in the brachial artery could be used as a surrogate for that in a coronary artery and as a prognostic marker for cardiovascular events. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.ijcard.2016.06.050

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

Recent studies have reported increases of methylglyoxal (MGO) in peritoneal dialysis patients, and that MGO-mediated inflammation plays an important role in the development of peritoneal fibrosis through production of transforming growth factor-beta 1 (TGF-beta 1). Linagliptin, a dipeptidyl peptidase-4 inhibitor, exerts anti-inflammatory effects independent of blood glucose levels. In this study, we examined whether linagliptin suppresses MGO-induced peritoneal fibrosis in mice. Male C57/BL6 mice were divided into three groups: control, MGO injection plus saline, and MGO injection plus linagliptin (n = 6 per group). Peritoneal fibrosis was induced by daily intraperitoneal injection of saline containing 40 mmol/L MGO for 21 days. Saline was administered intraperitoneally to the control group. Linagliptin (10 mg/kg) or saline were administrated by once-daily oral gavage from 3 weeks before starting MGO injections. Immunohistochemical staining revealed that linagliptin suppressed expression of a-smooth muscle actin and fibroblast-specific protein-1, deposition of type I and III collagen, and macrophage (F4/80) infiltration. Peritoneal equilibration testing showed improved peritoneal functions in mice treated with linagliptin. Peritoneal injection of MGO increased plasma levels of glucagon-like peptide-1 (GLP-1) in mice, and a further increase was observed in linagliptin-treated mice. Although MGO increased plasma glucose levels, linagliptin did not decrease plasma glucose levels. Moreover, linagliptin reduced the TGF-beta 1 concentration in the peritoneal fluid of MGO-treated mice. GLP-1 receptor (GLP-1R) was expressed in monocytes/macrophages and linagliptin suppressed GLP-1R expression in MGO-injected mice. These results suggest that oral administration of linagliptin ameliorates MGO-induced peritoneal fibrosis.

DOI： 10.1371/journal.pone.0160993

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

Background and aims: It is established that low-density lipoprotein cholesterol is an independent risk factor for cardiovascular events. Recently, circulating triglycerides level has been focused on as a risk factor for cardiovascular events. In this study, we evaluated the associations between triglycerides and endothelial function in a general population.
Methods: We analyzed data for 4887 subjects who were enrolled in the FMD-Japan registry. We investigated cross-sectional associations between serum triglyceride levels and endothelial function assessed by measurement of flow-mediated vasodilation (FMD).
Results: Serum triglyceride levels were correlated with FMD (r = -0.12, p &lt; 0.001). Subjects were divided into six groups based on serum triglyceride levels. FMD was significantly decreased with an increase in serum triglyceride levels (&lt;= 0.71 mmol/L, 7.0 +/- 3.5%; 0.72-0.94 mmol/L, 6.3 +/- 3.5%; 0.95-1.19 mmol/L, 6.0 +/- 3.1%; 1.20-1.48 mmol/L, 5.8 +/- 3.2%; 1.49-2.02 mmol/L, 5.7 +/- 3.1%; &gt;= 2.03 mmol/L, 5.5 +/- 3.0%; p for trend &lt;0.001). After adjustment for age, sex, and cardiovascular risk factors, including high-density lipoprotein cholesterol, serum triglyceride levels of more than 1.20 mmol/L were independently associated with the low quartile of FMD (1.20-1.48 mmol/L, odds ratio (OR) 1.41, 95% confidence interval (CI) 1.09 to 1.82; 1.49-2.02 mmol/L, OR 1.31, 95% CI 1.00 to 1.70; &gt;= 2.03 mmol/L, OR 1.48, 95% CI 1.13 to 1.95) using serum triglyceride levels of less than 0.71 mmol/L group as the reference.
Conclusions: These findings suggest that triglycerides are an independent predictor of endothelial function. Lowering circulating triglyceride levels may improve endothelial function, leading to a decrease in cardiovascular events. Clinical trial registration information: URL for Clinical Trial: http://UMIN; Registration Number for Clinical Trial: UMIN000003409 (C) 2016 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.atherosclerosis.2016.03.035

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

This study was undertaken to determine whether perinatal maternal resveratrol (Resv)a phytoalexin known to confer cardiovascular protectioncould prevent the development of hypertension and improve vascular function in adult spontaneously hypertensive rat offspring. Dams were fed either a control or Resv-supplemented diet (4 g/kg diet) from gestational day 0.5 until postnatal day 21. Indwelling catheters were used to assess blood pressure and vascular function in vivo; wire myography was used to assess vascular reactivity ex vivo. Perinatal Resv supplementation in dams had no effect on fetal body weights, albeit continued maternal treatment postnatally resulted in growth restriction in offspring by postnatal day 21; growth restriction was no longer evident after 5 weeks of age. Maternal perinatal Resv supplementation prevented the onset of hypertension in adult offspring (-18 mm Hg; P=0.007), and nitric oxide synthase inhibition (with l-NG-nitroarginine methyl ester) normalized these blood pressure differences, suggesting improved nitric oxide bioavailability underlies the hemodynamic alterations in the Resv-treated offspring. In vivo and ex vivo, vascular responses to methylcholine

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1161/HYPERTENSIONAHA.115.06839

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

High glucose (HG) induces production of transforming growth factor-beta1 (TGF-beta 1), but the mechanism remains elusive. The aim of this study was to determine the gene(s) involved in HG-induced TGF-beta 1 production in human peritoneal mesothelial cells (HPMCs).
Microarray analysis was performed following a 3-h preincubation of HPMCs in 4 or 0.1 % glucose medium. Transcriptional genes were selected using Gene Ontology analysis for biological processes, including regulation of transcription and DNA-dependent. The effects of small interfering RNA (siRNA) treatments on the up-regulation of TGF-beta 1 mRNA were assessed by quantitative real-time polymerase chain reaction (qPCR). Finally, enzyme-linked immunosorbent assay (ELISA) was performed to determine which gene(s) contribute to the production of TGF-beta 1 protein in the medium.
Microarray analysis revealed that the expression of 51 genes increased by more than 3-fold. Gene ontology analysis identified 13 genes for further study. qPCR confirmed mRNA amplification for 9 of the 13 genes. Furthermore, HG-induced up-regulation of TGF-beta 1 mRNA was attenuated by the siRNA of 4 genes: MDS1 and EVI1 complex locus (MECOM), FBJ murine osteosarcoma viral oncogene homolog B (FOSB), FBJ murine osteosarcoma viral oncogene homolog (FOS) and activating transcription factor 3 (ATF3). ELISA showed that siRNA treatment of FOS, but not MECOM, FOSB or ATF3, suppressed the increase of TGF-beta 1 protein in the medium.
FOS is a downstream effector of HG stimulation in HPMCs that contributes to TGF-beta 1 production, suggesting that blocking FOS expression may be a therapeutic target for peritoneal fibrosis.

DOI： 10.1007/s10157-015-1128-9

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

H3K9 methyltransferase G9a is reportedly induced by transforming growth factor-beta 1 (TGF-beta 1) and has an important role in the development of epithelial-mesenchymal transposition in cancer cells. Since the transcriptional activity of the Klotho gene is regulated by H3K9 modification, we investigated the effects of G9a on renal fibrosis and klotho expression. G9a levels were significantly upregulated by day 7 in the kidneys of unilateral ureteral-obstructed mice, but this was inhibited by TGF-beta 1-neutralizing antibody. Administration of G9a small interfering RNA not only decreased a-smooth muscle actin and fibronectin but also increased klotho expression in the ureteral-obstructed mice. Similarly, intraperitoneal injection of BIX01294, a specific inhibitor of G9a, showed beneficial effects on renal fibrosis and klotho expression with decreased monomethylation of H3K9 (me1). In in vitro experiments, BIX01294 also inhibited TGF-beta 1-induced fibrotic changes and klotho downregulation along with suppressed H3K9me1. In human kidney biopsy specimens, areas of G9a immunostaining correlated positively with H3K9me1 levels, as well as fibrotic markers, but correlated negatively with klotho expression. Thus, TGF-beta 1-induced G9a has an important role in the progression of renal fibrosis and reduced klotho expression through H3K9me1.

DOI： 10.1038/ki.2015.291

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC NEPHROLOGY  

TGF-beta 1 activity results in methylation of lysine 4 of histone H3 (H3K4) through SET domain containing lysine methyltransferase 7/9 (SET7/9) induction, which is important for the transcriptional activation of fibrotic genes in vitro. However, in vivo studies utilizing an experimental model of renal fibrosis are required to develop therapeutic interventions that target SET7/9. In this study, we investigated the signaling pathway of TGF-beta 1-induced SET7/9 expression and whether inhibition of SET7/9 suppresses renal fibrosis in unilateral ureteral obstruction (UUO) mice and kidney cell lines. Among the SET family, SET7/9 was upregulated on days 3 and 7 in UUO mice, and the upregulation was suppressed by TGF-beta 1 neutralizing antibody. TGF-beta 1 induced SET7/9 expression via Smad3 in normal rat kidney (NRK)-52E cells. In human kidney biopsy specimens from patients diagnosed with IgA nephropathy and membranous nephropathy, SET7/9 expression was positively correlated with the degree of interstitial fibrosis (r=0.59, P=0.001 in patients with IgA nephropathy; and r=0.58, P&lt;0.05 in patients with membranous nephropathy). In addition, small interfering RNA-mediated knockdown of SET7/9 expression significantly attenuated renal fibrosis in UUO mice. Sinefungin, an inhibitor of SET7/9, also suppressed the expression of mesenchymal markers and extracellular matrix proteins and inhibited H3K4 mono-nnethylation (H3K4me1) in kidneys of UUO mice. Moreover, sinefungin had an inhibitory effect on TGF-beta 1-induced a-smooth . muscle actin expression and H3K4me1 in both NRK-52E and NRK-49F cells. In conclusion, sinefungin, a SET7/9 inhibitor, ameliorates renal fibrosis by inhibiting H3K4me1 and may be a candidate therapeutic agent.

DOI： 10.1681/ASN.2014090850

Web of Science

記述言語：日本語   掲載種別：（MISC）研究発表要旨（全国大会，その他学術会議）  

J-GLOBAL

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN ATHEROSCLEROSIS SOC  

Aim: Both vascular function and structure are independent predictors of cardiovascular events. The purpose of this study was to evaluate vascular function and structure of a leg artery in patients with peripheral artery disease (PAD).
Methods: We measured flow-mediated vasodilatation (FMD) and nitroglycerine-induced vasodilation (NID) as indices of vascular function and intima-media thickness (IMT) as an index of vascular structure of the popliteal artery in 100 subjects, including 20 patients with Buerger disease and 30 patients with atherosclerotic PAD, 20 age-and sex-matched subjects without Buerger disease (control group) and 30 age-and sex-matched patients without atherosclerotic PAD (control group).
Results: IMT was significantly larger in the Buerger group than in the control group (Buerger, 0.63 +/- 0.20 mm; control, 0.50 +/- 0.07 mm; P=0.01), whereas there were no significant differences in FMD and NID between the two groups. IMT was significantly larger in the atherosclerotic PAD group than in the control group (atherosclerotic PAD, 0.80 +/- 0.22 mm; control, 0.65 +/- 0.14 mm; P &lt; 0.01), and FMD and NID were significantly smaller in the atherosclerotic PAD group than in the control group (FMD: atherosclerotic PAD, 3.9% +/- 1.1%; control, 5.0% +/- 1.8%; P &lt; 0.01; and NID: atherosclerotic PAD, 6.1% +/- 2.0%; control, 8.4% +/- 2.1%; P &lt; 0.01).
Conclusion: These findings suggest that vascular function is preserved in patients with Buerger disease and that both vascular function and vascular structure are impaired in patients with atherosclerotic PAD.

DOI： 10.5551/jat.35436

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Aim: A survey of hepatitis B virus (HBV) infection in hemodialysis (HD) patients was conducted to determine the burden and risk of infection and to suggest preventive measures against HBV infection among HD patients at nine hospitals in Hiroshima, Japan, from 1999 to 2003.
Methods: HBV markers were investigated for 1860 HD patients. The prevalence, incidence of HBV and prevalence of occult HBV were calculated.
Results: The prevalence of hepatitis B surface antigen (HBsAg) was 2.6%, the positive rate of anti-hepatitis B core (HBc) was 20.6% and that of anti-hepatitis B surface (HBs) was 11.7%. Among 1372 patients who started HD after the approval of erythropoietin in Japan in 1991, the prevalence of HBsAg was 2.1%. The incidence rate of HBsAg positivity was 0/1000 person-years and the incidence of anti-HBc was 0.3/1000 person-years. Among 1812 HBsAg negative patients HBV DNA was detected in two: one case was negative for anti-HBc and anti-HBs, and the other was only positive for anti-HBc. Prevalence of occult HBV was 0.11%.
Conclusion: The incidence rate of HBV was much lower than that of hepatitis C virus (HCV) in the same cohort. We supposed that the discrepancy between incidence rate of HBV and that of HCV was caused by the difference of their carrier rates and of their characteristics for persistent infection. So, we concluded that it is prerequisite to grasp the burden of HBV carriers in the group to prevent new HBV infections in HD patients.

DOI： 10.1111/hepr.12492

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Nitroglycerine-induced vasodilation (NID) is usually measured as a control test for flow-mediated vasodilation (FMD). However, NID per se is also associated with atherosclerosis. The purpose of this study was to determine the relationships among NID, FMD and blood pressure, and to evaluate the effects of antihypertensive therapy on NID in patients with hypertension. We measured NID and FMD simultaneously in 94 subjects, including 35 normotensive subjects, 26 patients with stage 1 hypertension (&gt;= 140/90mmHg) and 33 patients with stage 2 hypertension (&gt;= 160/100mmHg), and we evaluated the effect of antihypertensive therapy for 4 weeks on vascular function in 14 patients with hypertension. NID was smaller in patients with stage 2 hypertension than in patients with stage 1 hypertension and normotensive subjects (10.5 +/- 3.9% vs. 13.8 +/- 5.0% and 16.2 +/- 5.7%; P&lt;0.05, respectively), whereas there was no significant difference in NID between normotensive subjects and patients with stage 1 hypertension. FMD was smaller in patients with stage 2 and stage 1 hypertension than in normotensive subjects (3.1 +/- 2.7% and 4.1 +/- 1.5% vs. 6.4 +/- 2.7%; P&lt;0.05, respectively), whereas there was no significant difference in FMD between patients with stage 1 hypertension and those with stage 2 hypertension. After 4 weeks of antihypertensive therapy, NID was enhanced from 11.9 +/- 3.4% to 14.0 +/- 3.7% (P=0.03) in patients with hypertension. There was a significant relationship between the decrease in diastolic blood pressure and the increase in NID (r=-0.35, P=0.04). Both NID and FMD were impaired in patients with stage 2 hypertension. Four-week antihypertensive therapy improved NID in patients with hypertension.

DOI： 10.1038/hr.2015.93

Web of Science

記述言語：英語   掲載種別：（MISC）研究発表要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

記述言語：英語   掲載種別：（MISC）研究発表要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

記述言語：英語   掲載種別：（MISC）研究発表要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

記述言語：英語   掲載種別：（MISC）研究発表要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Chronic kidney disease patients share clinical and pathological features with the general aging population. Increased oxidative DNA damage, accumulation of cell cycle-arrested cells and decreased Klotho expression are assumed to be age-related factors that are reportedly linked to kidney disease. This study sought to determine the association between these age-related factors and renal damage in patients with IgA nephropathy (IgAN).
We performed a cross-sectional analysis of 71 patients who were diagnosed with IgAN by renal biopsy. Expression of 8-hydroxydeoxyguanosine (8-OHdG, a marker of oxidative DNA damage), p16 (a marker of cell cycle-arrest) and Klotho (an anti-aging protein) were evaluated by immunohistochemical staining of renal biopsy samples. We correlated the changes in expression of these markers with Lee's pathologic grades and the Oxford classification. We also investigated the independent association between these markers and interstitial fibrosis using multiple linear regression analysis.
8-OHdG and p16 increased but Klotho decreased with progression of pathologic grade. Expression of 8-OHdG and p16 increased with the deterioration of mesangial hypercellularity and segmental glomerulosclerosis. In addition, p16 increased but Klotho decreased with progression of tubular atrophy/interstitial fibrosis. In univariate regression analysis, age, body mass index, systolic blood pressure, urinary protein excretion and expression of 8-OHdG, p16 and Klotho showed significant correlations with interstitial fibrosis. Multivariable regression analyses revealed that aging, increased renal expression of p16 and decreased expression of Klotho were independently correlated with interstitial fibrosis.
The age-related factors might play important roles in the development of IgAN.

DOI： 10.1007/s10157-014-1070-2

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Rho-associated kinases play an important role in a variety of cellular functions. Although Rho-associated kinase activity has been shown to be an independent predictor for future cardiovascular events in a general population, there is no information on Rho-associated kinase activity in patients with acute coronary syndrome. We evaluated leukocyte Rho-associated kinase activity by Western blot analysis in 73 patients with acute coronary syndrome and 73 age- and gender-matched control subjects. Rho-associated kinase activity within 2 hours of acute coronary syndrome onset was higher in patients with acute coronary syndrome than in the control subjects (0.95 +/- 0.55 versus 0.69 +/- 0.31; P&lt;0.001). Rho-associated kinase activity promptly increased from 0.95 +/- 0.55 to 1.11 +/- 0.81 after 3 hours and reached a peak of 1.21 +/- 0.76 after 1 day (P=0.03 and P=0.03, respectively) and then gradually decreased to 0.83 +/- 0.52 after 7 days, 0.78 +/- 0.42 after 14 days, and 0.72 +/- 0.30 after 6 months (P=0.22, P=0.29, and P=0.12, respectively). During a median follow-up period of 50.8 months, 31 first major cardiovascular events (death from cardiovascular causes, myocardial infarction, ischemic stroke, and coronary revascularization) occurred. After adjustment for age, sex, cardiovascular risk factors, and concomitant treatment with statins, increased Rho-associated kinase activity was associated with increasing risk of first major cardiovascular events (hazard ratio, 4.56; 95% confidence interval, 1.98-11.34; P&lt;0.001). These findings suggest that Rho-associated kinase activity is dramatically changed after acute coronary syndrome and that Rho-associated kinase activity could be a useful biomarker to predict cardiovascular events in Japanese patients with acute coronary syndrome.

DOI： 10.1161/HYPERTENSIONAHA.115.05587

Web of Science

記述言語：日本語   掲載種別：（MISC）研究発表要旨（全国大会，その他学術会議）   出版者・発行元：(一社)日本心臓病学会  

記述言語：日本語   掲載種別：（MISC）研究発表要旨（国際会議）   出版者・発行元：(一社)日本心臓病学会  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Combination therapy of aliskiren and an angiotensin II receptor blocker (ARB) has been reported to be effective for reducing the level of proteinuria. However, it remains unclear whether this combination therapy contributes to suppression of kidney disease progression. The aim of this study was to investigate the effect of aliskiren on hard renal endpoints, when added to an ARB, in patients with advanced chronic kidney disease (CKD).
The study design was a prospective, randomized open-label design. 83 CKD patients (52 men and 31 women) were enrolled and assigned randomly to an aliskiren add-on group (n = 42) or control group (n = 41). Entry criteria included elevated serum creatinine a parts per thousand yen1.5 mg/dl, urine protein excretion (a parts per thousand yen1+ on urine dipstick test), and hypertension. All participants were treated with an ARB. The follow-up period was 12 months. 12 participants were withdrawn during the study period and the study was terminated in January 2012 as a consequence of the results of the interim analysis of the ALTITUDE study.
Nine patients in the aliskiren group and seven patients in the control group started dialysis. Doubling of the serum creatinine level occurred in one patient in the control group. A Cox proportional hazards test showed that dual blockade of the renin-angiotensin-aldosterone system with aliskiren and ARB was not associated with improvement in hard renal endpoints.
We conclude that aliskiren add-on therapy to an ARB may not give any benefit and, therefore, should not be recommended in CKD patients.

DOI： 10.1007/s10157-014-1044-4

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

The RhoA/Rho-associated kinase (ROCK) pathway has a key physiological role in the pathogenesis of atherosclerosis. Increased ROCK activity is associated with cardiovascular diseases. Endogenous nitric oxide (NO) has an anti-atherosclerotic effect, whereas the exogenous NO-mediated cardiovascular effect still remains controversial. The purpose of this study was to evaluate the effect of exogenous NO on ROCK activity in patients with angina pectoris. This is a prospective, open-label, randomized, controlled study. A total of 30 patients with angina pectoris were randomly assigned to receive 40 mg day(-1) of isosorbide mononitrate (n=15, 12 men and 3 women, mean age of 63 +/- 12 years, isosorbide mononitrate group) or conventional treatment (n=15, 13 men and 2 women, mean age of 64 +/- 13 years, control group) for 12 weeks. ROCK activity in peripheral leukocytes was measured by western blot analysis. ROCK activities at 4 and 12 weeks after treatment were decreased in the isosorbide mononitrate group (0.82 +/- 0.33 at 0 week, 0.62 +/- 0.20 at 4 weeks, 0.61 +/- 0.19 at 12 weeks, n=15 in each group, P&lt;0.05, respectively) but not altered in the control group. ROCK1 and ROCK2 expression levels were similar in all treatment periods in the two groups. These findings suggest that the administration of exogenous NO can inhibit ROCK activity, indicating that the usage of exogenous NO could have a protective effect in patients with angina pectoris.

DOI： 10.1038/hr.2015.24

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1161/HYPERTENSIONAHA.114.05001

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER DIABETES ASSOC  

OBJECTIVE
Advanced glycation end products (AGEs) and their specific receptor, the receptor for AGEs (RAGE), play an important role in atherosclerosis. Recently, a soluble form of RAGE (sRAGE) has been identified in human serum. However, the role of sRAGE in cardiovascular disease is still controversial. There is no information on the association between simultaneous measurements of AGEs and sRAGE and vascular function. In this study, we evaluated the associations between serum levels of AGEs and sRAGE, ratio of AGEs to sRAGE, and vascular function.
RESEARCH DESIGN AND METHODS
We measured serum levels of AGEs and sRAGE and assessed vascular function by measurement of flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation in 110 subjects who underwent health examinations. Multivariate regression analyses were performed to identify factors associated with vascular function.
RESULTS
Univariate regression analysis revealed that FMD correlated with age, BMI, systolic blood pressure, diastolic blood pressure, heart rate, triglycerides, HDL cholesterol, glucose, smoking pack-years, nitroglycerine-induced vasodilation, serum levels of AGEs and sRAGE, and ratio of AGEs to sRAGE. Multivariate analysis revealed that the ratio of AGEs to sRAGE remained an independent predictor of FMD, while serum level of AGEs alone or sRAGE alone was not associated with FMD.
CONCLUSIONS
These findings suggest that sRAGE may have a counterregulatory mechanism that is activated to counteract the vasotoxic effect of the AGE-RAGE axis. The ratio of AGEs to sRAGE may be a new chemical biomarker of endothelial function.

DOI： 10.2337/dc14-1435

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

Objective Although lipid disorders are a well-known risk factor for cardiovascular disease (CVD) in the general population, the optimal management with lipid-lowering therapy to reduce CVD risks and mortality in hemodialysis (HD) patients remains controversial. In the clinical setting, dyslipidemia can be diagnosed based on the detection of elevated lipid concentrations at the beginning of HD. This study investigated changes in the levels of serum lipids during a single HD session.
Methods The serum total cholesterol, triglyceride and high-density lipoprotein (HDL) cholesterol levels were measured in 31 HD patients at zero, two and four hours after the beginning of a single HD session. The data were analyzed using the Wilcoxon signed-rank test, a linear mixed model and Spearman's rank correlation analysis.
Results The serum total cholesterol, HDL cholesterol and non-HDL cholesterol levels increased significantly during the HD session. Even after the lipid parameters were corrected for changes in the total protein level, the total cholesterol and HDL cholesterol levels increased, whereas the non-HDL cholesterol levels did not change significantly. The percentage change in the serum levels of these lipid fractions correlated strongly with the percentage change in the ultrafiltration volume per body weight. In contrast, the serum triglyceride levels were decreased significantly at two hours compared with the levels noted at the beginning of HD and gradually increased at four hours.
Conclusion The serum lipid levels are influenced significantly by HD treatment and ultrafiltration. Evaluating the degree of dyslipidemia at the beginning of a HD session may therefore underestimate the levels of serum lipids in HD patients with a large amount of weight gain, thus resulting in the use of insufficient lipidlowering therapy.

DOI： 10.2169/internalmedicine.54.2997

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC NEPHROLOGY  

Background and objectives Telomeric G-tails play a pivotal role in maintaining the intramolecular loop structure of telomeres. Previous in vitro studies have suggested that the erosion of telomeric G-tails triggers cellular senescence, leading to organ dysfunction and atherosderosis. The authors recently established a method to measure telomeric G-tail length using a hybridization protection assay. Using this method, this study investigated whether telomeric G-tail length could be used as a novel predictor for future cardiovascular events in hemodialysis patients.Design, setting, participants, & measurements A prospective observational study was performed involving a cohort of 203 Japanese hemodialysis patients to examine the lengths of telomeric G-tails and total telomeres and subsequent cardiovascular events during a median follow-up period of 48 months. The lengths of telomeric G-tails and total telomeres were also measured in 203 participants who did not have CKD and who were age- and sex-matched to hemodialysis patients.Results The lengths of telomeric G-tails and total telomeres were significantly shorter in hemodialysis patients than in control subjects. Telomeric G-tails, but not total telomeres, were independently and negatively associated with clinical history of cardiovascular disease. During follow-up, 80 cardiovascular events occurred. Total telomere length did not predict cardiovascular events. However, the length of telomeric G-tails was associated with new-onset cardiovascular events (hazard ratio per log luminescence signals, 0.12; 95% confidence interval, 0.12 to 0.50) that persisted after adjustment for age, sex, diabetes mellitus, clinical history of cardiovascular disease, inflammation, use of vitamin D, and serum levels of phosphate and intact parathyroid hormone.Conclusions Longer telomeric G-tail length is associated with a lower risk of future cardiovascular events in hemodialysis patients.

DOI： 10.2215/CJN.10010913

Web of Science

記述言語：英語   掲載種別：（MISC）研究発表要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

記述言語：英語   掲載種別：（MISC）研究発表要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

記述言語：英語   掲載種別：（MISC）研究発表要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

記述言語：英語   掲載種別：（MISC）研究発表要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

記述言語：英語   掲載種別：（MISC）研究発表要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

Objective: Rho-associated kinase (ROCK) signaling pathway has been shown to mediate various cellular functions including cell proliferation, migration, adhesion, apoptosis, and contraction, all of which may be involved in pathogenesis of atherosclerosis. Endogenous nitric oxide (NO) is well known to have an anti-atherosclerotic effect, whereas the exogenous NO-mediated cardiovascular effect still remains controversial. The purpose of this study was to evaluate the effect of exogenous NO on ROCK activity in vascular smooth muscle cells (VSMCs) in vitro and in vivo.
Methods: VSMCs migration was evaluated using a modified Boyden chamber assay. ROCK activities were measured by Western blot analysis in murine and human VSMCs and aorta of mice treated with or without angiotensin II (Ang II) and/or sodium nitroprusside (SNP), an NO donor.
Results: Co-treatment with SNP inhibited the Ang II-induced cell migration and increases in ROCK activity in murine and human VSMCs. Similarly, the increased ROCK activity 2 weeks after Ang II infusion in the mouse aorta was substantially inhibited by subcutaneous injection of SNP.
Conclusions: These findings suggest that administration of exogenous NO can inhibit ROCK activity in VSMCs in vitro and in vivo.

DOI： 10.1371/journal.pone.0109017

Web of Science

記述言語：日本語   掲載種別：（MISC）研究発表要旨（全国大会，その他学術会議）   出版者・発行元：(NPO)日本高血圧学会  

記述言語：日本語   掲載種別：（MISC）研究発表要旨（全国大会，その他学術会議）   出版者・発行元：(一社)日本心臓病学会  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPANESE CIRCULATION SOC  

Background: An ankle-brachial index (ABI) value of 0.91-0.99 is considered borderline and associated with an increased risk of cardiovascular events. However, there is no information on the relationship between borderline ABI and endothelial function.
Methods and Results: We measured ABI and assessed vascular function by flow-mediated vasodilation (FMD) and nitroglycerin-induced vasodilation in 389 subjects who underwent health examinations. Subjects were divided into 3 groups according to ABI (normal group: 1.00-1.40, borderline group: 0.91-0.99, abnormal group: &lt;= 0.90 or &gt;1.40). FMD was significantly smaller in both the borderline and the abnormal group than in the normal group. There was no significant difference in the vascular responses to nitroglycerin between the normal and borderline groups. Vascular response to nitroglycerin was significantly higher in the normal group than in the abnormal group. Borderline and abnormal ABI values were significantly associated with an increased odds ratio of low tertile of FMD levels, using the normal ABI group as the reference. Multiple logistic regression analysis for FMD revealed that age, sex, hypertension, diabetes mellitus, and borderline ABI independently remained associated with FMD.
Conclusions: ABI of 0.91-0.99 is associated with endothelial dysfunction. ABI examination is a simple and cost-effective method for obtaining the additional information on the initial step of atherosclerosis beyond the assessment of peripheral artery disease.

DOI： 10.1253/circj.CJ-14-0165

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

Objective: Nitroglycerine-induced vasodilation is usually used as a control test for flow-mediated vasodilation (FMD). However, nitroglycerine-induced vasodilation per se has also been reported to be impaired in patients with atherosclerosis. The purpose of this study was to determine the relationship between nitroglycerine-induced vasodilation and the clinical severity of peripheral artery disease (PAD).
Methods and results: We measured nitroglycerine-induced vasodilation and FMD in 144 subjects (mean age: 63.8 +/- 15.1 years), including 32 PAD patients with critical limb ischemia (CLI group), 28 PAD patients without CLI (non-CLI group), 60 age- and sex-matched patients without established cardiovascular disease (at-risk group), and 24 healthy subjects (healthy group). Nitroglycerine-induced vasodilation was significantly impaired in the CLI group compared to that in the other three groups (healthy group, 16.0 +/- 5.3%; at-risk group, 12.9 +/- 3.8%; non-CLI group, 10.3 +/- 5.1%; CLI group, 6.7 +/- 3.9%; P &lt; 0.05, respectively). Even after multivariate adjustment, the differences remained significant. On the other hand, FMD was significantly impaired in the at-risk, non-CLI, and CLI group compared with that in the healthy group (healthy group, 7.1 +/- 2.9%; at-risk group, 3.4 +/- 2.3%; non-CLI group, 3.5 +/- 2.7%; CLI group, 3.0 +/- 2.8%; P &lt; 0.001, respectively), but the differences among the at-risk, non-CLI, and CLI groups were not significant. Multivariate analysis revealed that nitroglycerine-induced vasodilation (odds ratio: 0.77, 95% confidence interval [CI]: 0.61-0.97) and diabetes mellitus (odds ratio: 8.75, 95% CI: 1.74-44.2) were independent variables for CLI in PAD patients.
Conclusions: There was no significant difference in FMD between PAD patients with and those without CLI, but nitroglycerine-induced vasodilation was significantly smaller in PAD patients with CLI compared with those without CLI. (C) 2014 Published by Elsevier Ireland Ltd.

DOI： 10.1016/j.atherosclerosis.2014.04.012

Web of Science

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Low serum testosterone levels have been recently linked to endothelial dysfunction, arterial stiffness, and worse outcomes in male hemodialysis patients. We tested the hypothesis that low serum testosterone levels are also associated with atherosclerosis risk factors in postmenopausal women undergoing hemodialysis.
We measured serum testosterone in 115 confirmed postmenopausal ethnically Japanese women undergoing hemodialysis with mean age of 68.1 +/- A 10.6 years and median dialysis vintage of 73 months. The severity of atherosclerosis was evaluated by carotid intima-media thickness (cIMT) and cardio-ankle vascular index (CAVI). In addition, we also included a control cohort of 32 age-matched postmenopausal women without chronic kidney disease.
Serum testosterone was significantly lower in women undergoing hemodialysis than in age-matched controls. Women undergoing hemodialysis who had undetectable testosterone concentration presented higher cIMT and higher CAVI than women undergoing hemodialysis with testosterone concentration above detection limits (P &lt; 0.05 for all). Multiple logistic regression analyses confirmed the independence of these associations.
Serum testosterone levels in postmenopausal women undergoing hemodialysis are abnormally low and associated with features of atherosclerosis.

DOI： 10.1007/s10157-013-0840-6

Web of Science

記述言語：日本語   掲載種別：（MISC）総説・解説（学術雑誌）   出版者・発行元：(一社)日本腎臓学会  

記述言語：英語   掲載種別：（MISC）研究発表要旨（国際会議）   出版者・発行元：WILEY  

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

Aldosterone-salt treatment induces not only hypertension but also extensive inflammation that contributes to fibrosis in the rat kidney. However, the mechanism underlying aldosterone-salt-induced renal inflammation remains unclear. Pyroptosis has recently been identified as a new type of cell death that is accompanied by the activation of inflammatory cytokines. We hypothesized that aldosterone-salt treatment could induce inflammation through pyroptosis and that mizoribine, an effective immunosuppressant, would ameliorate the renal inflammation that would otherwise cause renal fibrosis. Ten days after recovery from left uninephrectomy, rats were given drinking water with 1% sodium chloride. The animals were divided into three groups (n=7 per group): (1) vehicle infusion group, (2) aldosterone infusion group, or (3) aldosterone infusion plus oral mizoribine group. Aldosterone-salt treatment increased the expression of the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 and caspase-1, and also increased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells. However, the oral administration of mizoribine attenuated these alterations. Furthermore, mizoribine inhibited hypertension and renal fibrosis, and also attenuated the aldosterone-induced expression of serum/glucocorticoid-regulated kinase and a epithelial sodium channel. These results suggest that caspase-1 activation plays an important role in the development of inflammation induced by aldosterone-salt treatment and that it functions as an anti-inflammatory strategy that protects against renal injury and hypertension.

DOI： 10.1371/journal.pone.0093513

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPANESE CIRCULATION SOC  

Background: Poor oral health is an independent predictor of cardiovascular outcome. Endothelial dysfunction is the initial step of atherosclerosis, resulting in cardiovascular outcomes; but there is no information on the association between oral health and endothelial function. The purpose of this study was to determine the relationships between oral health and endothelial function.
Methods and Results: A total of 190 subjects who underwent health examinations (mean age, 57 +/- 18 years), including patients with cardiovascular disease, completed a questionnaire on oral health and frequency of tooth brushing, and underwent measurement of vascular function, flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation. The subjects were divided into 2 groups according to frequency of tooth brushing (&gt;= twice/day and &lt;once/day). FMD was significantly lower in the &lt;once/day tooth brushing group as compared to the &gt;= twice/day tooth brushing group (3.3 +/- 2.2% vs. 5.0 +/- 3.0%, P&lt;0.001). There was no significant difference in nitroglycerine-induced vasodilation between the 2 groups. On multiple logistic regression analysis, tooth brushing &lt;once/day remained independently associated with low FMD tertile.
Conclusions: Poor oral health, that is, decreased frequency of tooth brushing, is associated with endothelial dysfunction.

DOI： 10.1253/circj.CJ-13-1330

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Cardiovascular diseases are associated with chronic activation of Rho-associated kinase. Rho-associated kinase activity is significantly correlated with endothelial function and Framingham risk score. However, there is no information on the prognostic value of Rho-associated kinase activity. We evaluated Rho-associated kinase activity in peripheral leukocytes by Western blot analysis in 633 subjects who underwent health-screening examination at Hiroshima University Hospital. We assessed the associations between Rho-associated kinase activity and first major cardiovascular events (death from cardiovascular causes, myocardial infarction, and stroke), death from cardiovascular causes, acute myocardial infarction, stroke, revascularization (percutaneous coronary intervention, coronary artery bypass grafting), and hospitalization for heart failure. During a median period of 42.0 months (interquartile range, 24.4-56.6 months) of follow-up, 29 subjects died (10 from cardiovascular causes), 2 myocardial infarction, 20 revascularization, 15 stroke, and 17 hospitalization for heart failure. After adjustment for age, sex, cardiovascular risk factors, and other relevant variables, Rho-associated kinase activity remained a strong independent indicator of first major cardiovascular events (hazard ratio, 2.19; 95% confidence interval, 1.35-3.70; P=0.002), death from cardiovascular disease (hazard ratio, 2.57; 95% confidence interval, 1.18-6.60; P=0.002), stroke (hazard ratio, 2.14; 95% confidence interval, 1.24-3.86; P=0.006), and revascularization (hazard ratio, 2.68; 95% confidence interval, 1.60-4.66; P&lt;0.001). Leukocyte Rho-associated kinase activity may be a new biomarker of cardiovascular events. These findings suggest that inhibition of Rho-associated kinase activity may be a therapeutic target for prevention of cardiovascular events.

DOI： 10.1161/HYPERTENSIONAHA.113.02296

Web of Science

記述言語：日本語   掲載種別：（MISC）研究発表要旨（全国大会，その他学術会議）   出版者・発行元：広島医学会  

記述言語：日本語   掲載種別：（MISC）研究発表要旨（全国大会，その他学術会議）  

J-GLOBAL

記述言語：日本語   掲載種別：（MISC）研究発表要旨（全国大会，その他学術会議）  

J-GLOBAL

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BMJ PUBLISHING GROUP  

Objective To determine the relationships between flow-mediated vasodilation (FMD) and cardiovascular risk factors, and to evaluate confounding factors for measurement of FMD in a large general population in Japan.
Methods This was a cross-sectional study. A total of 5314 Japanese adults recruited from people who underwent health screening from 1 April 2010 to 31 August 2012 at 3 general hospitals in Japan. Patients' risk factors (age, Body Mass Index, blood pressure, cholesterol parameters, glucose level and HbA1c level) and prevalence of cardiovascular disease (coronary heart disease and cerebrovascular disease) were investigated.
Results Univariate regression analysis revealed that FMD correlated with age (r=-0.27, p&lt;0.001), Body Mass Index (r=-0.14, p&lt;0.001), systolic blood pressure (r=-0.18, p&lt;0.001), diastolic blood pressure (r=-0.13, p&lt;0.001), total cholesterol (r=-0.07, p&lt;0.001), triglycerides (r=-0.10, p&lt;0.001), high-density lipoprotein cholesterol (r=0.06, p&lt;0.001), low-density lipoprotein cholesterol (r=-0.04, p=0.01), glucose level (r=-0.14, p&lt;0.001), HbA1c (r=-0.14, p&lt;0.001), and baseline brachial artery diameter (r=-0.43, p&lt;0.001) as well as Framingham Risk score (r=-0.29, p&lt;0.001). Multivariate analysis revealed that age (t value=-9.17, p&lt;0.001), sex (t value=9.29, p&lt;0.001), Body Mass Index (t value=4.27, p&lt;0.001), systolic blood pressure (t value=-2.86, p=0.004), diabetes mellitus (t value=-4.19, p&lt;0.001), smoking (t value=-2.56, p=0.01), and baseline brachial artery diameter (t value=-29.4, p&lt;0.001) were independent predictors of FMD.
Conclusions FMD may be a marker of the grade of atherosclerosis and may be used as a surrogate marker of cardiovascular outcomes. Age, sex, Body Mass Index, systolic blood pressure, diabetes mellitus, smoking and, particularly, baseline brachial artery diameter are potential confounding factors in the measurement of FMD.

DOI： 10.1136/heartjnl-2013-304739

Web of Science

記述言語：英語   掲載種別：（MISC）研究発表要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

記述言語：英語   掲載種別：（MISC）研究発表要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

We screened circadian-regulated genes in rat cartilage by using a DNA microarray analysis. In rib growth-plate cartilage, numerous genes showed statistically significant circadian mRNA expression under both 12:12 h light-dark and constant darkness conditions. Type II collagen and aggrecan genes-along with several genes essential for post-translational modifications of collagen and aggrecan, including prolyl 4-hydroxylase 1, lysyl oxidase, lysyl oxidase-like 2 and 3'-phosphoadenosine 5'-phosphosulphate synthase 2-showed the same circadian phase. In addition, the mRNA level of SOX9, a master transcription factor for the synthesis of type II collagen and aggrecan, has a similar phase of circadian rhythms. The circadian expression of the matrix-related genes may be critical in the development and the growth of various cartilages, because similar circadian expression of the matrix-related genes was observed in hip joint cartilage. However, the circadian phase of the major matrix-related genes in the rib permanent cartilage was almost the converse of that in the rib growth-plate cartilage under light-dark conditions. We also found that half of the oscillating genes had conserved clock-regulatory elements, indicating contribution of the elements to the clock outputs. These findings suggest that the synthesis of the cartilage matrix macromolecules is controlled by cell-autonomous clocks depending upon the in vivo location of cartilage.

DOI： 10.1093/jb/mvt068

Web of Science

記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

記述言語：日本語   掲載種別：（MISC）研究発表要旨（国際会議）   出版者・発行元：(NPO)日本高血圧学会  

記述言語：日本語   掲載種別：（MISC）研究発表要旨（全国大会，その他学術会議）   出版者・発行元：(NPO)日本高血圧学会  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

Background: It is clinically important to estimate the degree of endothelial dysfunction. Several methods have been used to assess endothelial function in humans. Recently, we developed a new noninvasive method for measurement of vascular response to reactive hyperemia in the brachial artery, named enclosed zone flow-mediated vasodilation (ezFMD). The purpose of this study was to determine the validity of ezFMD for assessment of endothelial function. Methods and results: We measured ezFMD by a new device using an oscillometric method and conventional FMD using ultrasonography in 306 subjects, including patients with hypertension, dyslipidemia, and diabetes mellitus (218 men and 88 women, 30±16yr). Univariate regression analysis revealed that ezFMD significantly correlated with age (r=-0.42, P&lt
0.0001), body mass index (r=-0.13, P=0.028), systolic blood pressure (r=-0.15, P=0.009), diastolic blood pressure (r=-0.14, P=0.011), fasting glucose level (r=-0.27, P=0.006), smoking (r=-0.21, P=0.007) and baseline pulse wave amplitude (r=-0.51, P&lt
0.0001). ezFMD significantly correlated with conventional FMD (r=0.34, P&lt
0.0001). Multiple regression analysis revealed that age (P=0.002), body mass index (P=0.013), systolic blood pressure (P=0.009), smoking (P=0.004) and baseline pulse wave amplitude (P&lt
0.001) were independent predictors of ezFMD. Conclusions: These findings suggest that measurement of ezFMD, a novel noninvasive and simple method, may be useful for determination of vascular diameter response to reactive hyperemia. Since ezFMD is automatically measured by a device with an oscillometric method, measurement of ezFMD is easier and less biased than that of conventional FMD. © 2013 Elsevier Ireland Ltd.

DOI： 10.1016/j.atherosclerosis.2013.05.016

Scopus

PubMed

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Mesenchymal stem cells (MSCs) are multipotent adult stem cells that have regenerative capability and exert paracrine actions on damaged tissues. Since peritoneal fibrosis is a serious complication of peritoneal dialysis, we tested whether MSCs suppress this using a chlorhexidine gluconate model in rats. Although MSCs isolated from green fluorescent protein-positive rats were detected for only 3 days following their injection, immunohistochemical staining showed that MSCs suppressed the expression of mesenchymal cells, their effects on the deposition of extracellular matrix proteins, and the infiltration of macrophages for 14 days. Moreover, MSCs reduced the functional impairment of the peritoneal membrane. Cocultures of MSCs and human peritoneal mesothelial cells using a Transwell system indicated that the beneficial effects of MSCs on the glucose-induced upregulation of transforming growth factor-beta 1(TGF-beta 1) and fibronectin mRNA expression in the human cells were likely due to paracrine actions. Preincubation in MSC-conditioned medium suppressed TGF-beta 1-induced epithelial-to-mesenchymal transition, alpha-smooth muscle actin, and the decrease in zonula occludens-1 in cultured human peritoneal mesothelial cells. Although bone morphogenic protein 7 was not detected, MSCs secreted hepatocyte growth factor and a neutralizing antibody to this inhibited TGF-beta 1 signaling. Thus, our findings imply that MSCs ameliorate experimental peritoneal fibrosis by suppressing inflammation and TGF-beta 1 signaling in a paracrine manner.

DOI： 10.1038/ki.2013.81

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

Background: The purpose of this study was to determine whether autologous mesenchymal stem cells (MSCs) implantation improves endothelial dysfunction in a rabbit ischemic limb model.
Methods: We evaluated the effect of MSC implantation on limb blood flow (LBF) responses to acetylcholine (ACh), an endothelium-dependent vasodilator, and sodium nitroprusside (SNP), an endothelium-independent vasodilator, in rabbits with limb ischemia in which cultured MSCs were implanted (n = 20) or saline was injected as a control group (n = 20). LBF was measured using an electromagnetic flowmeter. A total of 10(6) MSCs were implanted into each ischemic limb.
Results: Histological sections of ischemic muscle showed that capillary index (capillary/muscle fiber) was greater in the MSC implantation group than in the control group. Laser Doppler blood perfusion index was significantly increased in the MSC implantation group compared with that in the control group. LBF response to ACh was greater in the MSC group than in the control group. After administration of N-G-nitro-L-arginine, a nitric oxide synthase inhibitor, LBF response to ACh was similar in the MSC implantation group and control group. Vasodilatory effects of SNP in the two groups were similar.
Conclusions: These findings suggest that MSC implantation induces angiogenesis and augments endothelium-dependent vasodilation in a rabbit ischemic model through an increase in nitric oxide production.

DOI： 10.1371/journal.pone.0067739

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Objective-Nitroglycerine-induced vasodilation has been used as a control test for flow-mediated vasodilation (FMD) to differentiate endothelium-dependent from endothelium-independent response when evaluating endothelial function in humans. Recently, nitroglycerine-induced vasodilation has also been reported to be impaired in patients with atherosclerosis. The purpose of this study was to determine the relationships between nitroglycerine-induced vasodilation and cardiovascular risk factors. Approach and Results-We measured nitroglycerine-induced vasodilation and FMD in 436 subjects who underwent health examinations (mean age, 53±19 years
age range, 19-86 years), including patients with cardiovascular diseases. There was a significant relationship between nitroglycerine-induced vasodilation and FMD (r=0.42
P&lt
0.001). Univariate regression analysis revealed that nitroglycerine-induced vasodilation correlated with age (r=-0.34
P&lt
0.001), systolic blood pressure (r=-0.32
P&lt
0.001), diastolic blood pressure (r=-0.24
P&lt
0.001), heart rate (r=-0.21
P&lt
0.001), glucose (r=-0.23
P&lt
0.001), and smoking pack-year (r=-0.12
P=0.01), as well as Framingham risk score (r=-0.30
P&lt
0.001). Nitroglycerine-induced vasodilation was significantly smaller in patients with cardiovascular disease than in both subjects with and without cardiovascular risk factors (10.5±5.6% versus 13.7±5.4% and 15.3±4.3%
P&lt
0.001, respectively), whereas there was no significant difference in nitroglycerine-induced vasodilation between subjects with and without cardiovascular risk factors. Multivariate analysis revealed that male sex, body mass index, hypertension, diabetes mellitus, baseline brachial artery diameter, and FMD were independent predictors of nitroglycerine-induced vasodilation. Conclusions-These findings suggest that nitroglycerine-induced vasodilation may be a marker of the grade of atherosclerosis. FMD should be interpreted as an index of vascular function reflecting both endothelium-dependent vasodilation and endothelium-independent vasodilation in subjects with impaired nitroglycerine-induced vasodilation. © 2013 American Heart Association, Inc.

DOI： 10.1161/ATVBAHA.112.300934

Scopus

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPANESE CIRCULATION SOC  

Background: The purpose of this study was to evaluate the effect of anatomical variation of the brachial artery on flow-mediated vasodilation (FMD) in healthy subjects and patients with cardiovascular disease (CVD).
Methods and Results: There was no significant difference in the prevalence of double brachial artery between healthy subjects (6.1%) and patients with CVD (6.5%). In healthy subjects, FMD was larger in a single brachial artery than in large and small vessels of a double brachial artery (7.2 +/- 3.4% vs. 4.7 +/- 3.3% and 4.5 +/- 2.5%, P&lt;0.01, respectively). In patients with CVD, there were no significant differences in FMD among a single brachial artery, large vessel of a double brachial artery and small vessel of a double brachial artery (3.3 +/- 1.4%, 3.1 +/- 2.3% and 3.6 +/- 2.1%). FMD in a single brachial artery was smaller in patients with CVD than in healthy subjects. There were no significant differences in FMD in the large vessel of a double brachial artery between the 2 groups or in the small vessel of a double brachial artery between the 2 groups. Nitroglycerine-induced vasodilation was similar in all arteries in healthy subjects and patients with CVD.
Conclusions: When measuring FMD, the existence of a double brachial artery should be checked. FMD measured in a double brachial artery may be underestimated in healthy subjects. (Circ J 2013; 77: 1073-1080)

DOI： 10.1253/circj.CJ-12-1130

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BMJ PUBLISHING GROUP  

Objectives The purpose of this study was to determine the relationships between uric acid, endothelial function and cardiovascular risk factors and to investigate whether menopausal status was associated with the relationship between uric acid and endothelial function in women.
Design Cross-sectional study.
Setting 3 general hospitals in Japan.
Participants 749 Japanese women aged 30-74years recruited from people who underwent health-screening examinations with agreement for measurement of vascular function.
Measures We measured serum concentrations of uric acid and flow-mediated vasodilation (FMD). Percentage of FMD (peak diameter-baseline diameter/baseline diameter) was used for analysis. Endothelial dysfunction was defined as FMD 4.90%, division point for the lowest tertile and the middle tertile of FMD. Menopause women were defined as participants without menstruation for over 1year or participants with a history of hysterectomy or bilateral oophorectomy.
Results Of the 749 participants, 368 (49.1%) were premenopausal women and 381 (50.9%) were postmenopausal women. Age, body mass index, systolic blood pressure, total cholesterol, triglycerides, glucose, estimated glomerular filtration rate and Framingham risk score were significantly correlated with serum uric acid level. FMD showed a gradual decrease in accordance with the serum uric acid level in the entire study population (&lt;4mg/dL, 6.853.65%; 4 to &lt;5mg/dL, 6.793.60%; 5 to &lt;6mg/dL, 6.24 +/- 3.58%; 6mg/dL, 5.27 +/- 3.18%; p=0.01). Multivariate analysis revealed that uric acid was a significantly independent risk factor for endothelial dysfunction in postmenopausal women (OR 1.23, 95% CI 1.01 to 1.50), but not in premenopausal women.
Conclusions These findings suggest that uric acid can be used as a risk marker of endothelial dysfunction in a female population, and particularly as an independent risk factor in postmenopausal women but not in premenopausal women.

DOI： 10.1136/bmjopen-2013-003659

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

When diagnosing hypertension (HT) it is essential to determine not only the level of raised blood pressure (BP), but also how the condition relates to organ damage. The best time to measure BP for diagnosing HT in patients on hemodialysis (HD) remains unclear.
A total of 100 HD patients (mean age 63.8 years, 60 males) were studied. Left ventricular hypertrophy (LVH) was detected by echocardiography and BP monitored for 1 week at 20 different times in the morning and night, before and after dialysis. We also checked for masked HT, i.e., patients with weekly morning HT, but not pre-dialysis HT.
Average BP for the week was 141.9 +/- 19.0/79.6 +/- A 10.6 mmHg, with 68 patients classified as hypertensive. Average morning BP was 144.6 +/- A 19.8/81.7 +/- A 11.3 mmHg, and 71 patients had weekly morning HT. In addition, 62 patients had LVH and 51 patients had relative morning HT. Multiple logistic analyses showed that LVH was associated with weekly morning HT, morning HT on HD and non-HD days, average HT, and relative morning HT. However, evening, pre-dialysis, and post-dialysis HT showed no association with LVH. Masked HT was found in 20 % of patients. If HT had been diagnosed using only pre-dialysis BP, 20 of the 71 patients with weekly morning HT would not have been detected.
Morning BP is useful for detecting LVH in HD patients. Monitoring of morning BP may be superior to measurements taken at other times for diagnosing HT.

DOI： 10.1007/s10157-012-0639-x

Web of Science

記述言語：英語   掲載種別：（MISC）研究発表要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

記述言語：英語   掲載種別：（MISC）研究発表要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

記述言語：英語   掲載種別：（MISC）研究発表要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

記述言語：英語   掲載種別：（MISC）研究発表要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

記述言語：英語   掲載種別：（MISC）研究発表要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

記述言語：英語   掲載種別：（MISC）研究発表要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

記述言語：英語   掲載種別：（MISC）研究発表要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

記述言語：日本語   掲載種別：（MISC）総説・解説（学術雑誌）   出版者・発行元：(公社)日本超音波医学会  

記述言語：日本語   掲載種別：（MISC）総説・解説（学術雑誌）   出版者・発行元：(公社)日本超音波医学会  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Objective-Cardiovascular diseases are associated with impaired flow-mediated vasodilation (FMD) and increase in carotid intima-media thickness (IMT). Both FMD and IMT are independent predictors for cardiovascular outcomes. When measuring FMD and nitroglycerine-induced vasodilation in the brachial artery, IMT can also be simultaneously assessed in the same brachial artery. The purpose of this study was to determine the relationships between IMT of the brachial artery, vascular function, and cardiovascular risk factors.
Methods and Results-We measured brachial IMT, FMD, and nitroglycerine-induced vasodilation by ultrasound in 388 subjects who underwent health examination (mean age, 45 +/- 22 years; age range, 19-86), including patients with cardiovascular diseases. Univariate regression analysis revealed that brachial IMT significantly correlated with age (r=0.71; P&lt;0.001), body mass index (r=0.27; P&lt;0.001), systolic blood pressure (r=0.40; P&lt;0.001), diastolic blood pressure (r=0.31; P&lt;0.001), heart rate (r=0.15; P=0.002), glucose level (r=0.18; P=0.01), and smoking pack-years (r=0.42; P&lt;0.001), as well as Framingham risk score, a cumulative cardiovascular risk index for heart attack (r=0.49; P&lt;0.001). FMD and nitroglycerine-induced vasodilation were inversely associated with brachial IMT (r=-0.39, P&lt;0.001; r=-0.32, P&lt;0.001, respectively). In addition, there was a significant relationship between brachial IMT and carotid IMT (r=0.58; P&lt;0.001). Multivariate analysis revealed that age, sex, hypertension, and brachial artery diameter were independent predictors of brachial IMT.
Conclusion-These findings suggest that brachial IMT may be a marker of the grade of atherosclerosis and may be used as a marker of vascular function, providing additive information for stratifying subjects with cardiovascular risk factors. (Arterioscler Thromb Vasc Biol. 2012;32:2295-2303.)

DOI： 10.1161/ATVBAHA.112.249680

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Background-Patients with Gilbert syndrome have mild unconjugated hyperbilirubinemia. It has been shown that bilirubin is an endogenous antioxidant. We evaluated the role of oxidative stress in endothelial function in patients with Gilbert syndrome under normal conditions without cardiovascular risk factors.
Methods and Results-A total of 108 young men with Gilbert syndrome without cardiovascular risk factors and 108 age-matched healthy men (normal controls) were enrolled in this study. Serum concentrations of bilirubin were higher in patients with Gilbert syndrome than in control subjects (29.2 +/- 11.6 versus 9.4 +/- 2.7 mu mol/L; P&lt;0.001). Serum concentrations of malondialdehyde-modified low-density lipoprotein and urinary excretion of 8-hydroxy-2'-deoxyguanosine (8-OHdG), as indices of oxidative stress, were lower in patients with Gilbert syndrome than in control subjects (61.8 +/- 24.5 versus 72.5 +/- 21.8 U/L, P=0.034; 7.8 +/- 2.4 versus 10.4 +/- 3.2 ng/mg creatinine, P=0.001, respectively). Flow-mediated vasodilation was greater in patients with Gilbert syndrome than in normal control subjects (7.2 +/- 2.2% versus 5.9 +/- 1.7%; P&lt;0.001). Vascular responses to nitroglycerine were not significantly different between the 2 groups. Flow-mediated vasodilation correlated with serum concentration of bilirubin (r=0.44, P&lt;0.001), malondialdehyde-modified low-density lipoprotein (r=-0.25, P=0.01), and urinary excretion of 8-OHdG (r=-0.27, P=0.004) in patients with Gilbert syndrome but not in control subjects. In addition, serum concentration of bilirubin correlated with malondialdehyde-modified low-density lipoprotein (r=-0.20, P=0.04) and 8-OHdG (r=-0.21, P=0.02) in patients with Gilbert syndrome but not in control subjects.
Conclusions-Patients with Gilbert syndrome had low levels of oxidative stress associated with hyperbilirubinemia and enhancement of endothelium-dependent vasodilation.

DOI： 10.1161/CIRCULATIONAHA.112.105775

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

DEC1 and DEC2, members of the basic helix-loop-helix superfamily, are involved in various biological phenomena including clock systems, cell differentiation and metabolism. In clock systems, Dec1 and Dec2 expression are up-regulated by the CLOCK:BMAL1 heterodimer via E-box (CACGTG), exhibiting a circadian rhythm in the suprachiasmatic nucleus (SCN), the central circadian pacemaker and other peripheral tissues. In this study, using assays of luciferase reporters, electrophoretic mobility shift and chromatin immunoprecipitation, we identified novel nuclear receptor response elements, ROR response elements (RORE), in Dec1 and Dec2 promoters. These ROREs responded to the transcriptional activator RORa, but not to the repressor REVERBa, although the Bmal1 promoter responded to both RORa and REVERBa. Therefore, RORa, but not REVERBa, is involved in the regulation of Dec1 and Dec2 expression without significantly affecting their rhythmicity. Since RORa, DEC1 and DEC2 reportedly suppressed adipogenic differentiation, we examined expression of Rora, Dec1, Dec2 and other clock-controlled genes in differentiating 3T3-L1 adipocytes. The results suggested that RORa suppresses adipogenic differentiation at a later stage of differentiation by RORE-mediated stimulation of Dec1 and Dec2 expression.

DOI： 10.1111/j.1365-2443.2011.01574.x

Web of Science

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER LONDON LTD  

A high circulating osteoprotegerin (OPG) level may be a risk factor for vascular calcification and mortality in hemodialysis patients. OPG and pulse wave velocity (PWV) were measured at baseline in 151 normoalbuminemic, long-term (&gt; 3 years) Japanese hemodialysis patients who were prospectively followed for 6 years. In long-term normoalbuminemic Japanese hemodialysis patients, OPG levels were strongly linked with both arterial stiffness and worse outcome.
A high circulating OPG level is reported to be a risk factor for vascular calcification and mortality in Western chronic kidney disease (CKD) patients but it is not known if this is true for Japanese CKD patients, where a different risk profile may operate.
OPG and PWV were measured at baseline in 151 normoalbuminemic, long-term (&gt; 3 years) Japanese hemodialysis patients (median age 62 years) who were prospectively followed for 6 years.
OPG levels were associated in multivariate analysis with age, dialysis vintage, history of cardiovascular disease (CVD) and parathyroid hormone levels. C-reactive protein levels did not correlate with OPG. Patients with clinical history of CVD had significantly higher OPG levels and OPG levels were positively correlated to PWV, an index of arterial stiffness. These associations were independent of age, sex, dialysis vintage, and diabetes. During the follow-up period, 40 deaths, including 25 cardiovascular deaths, were recorded. In crude analysis, each unit of increase in OPG was associated with increased all-cause (hazard ratios 1.14, 95% confidence interval 1.08-1.20) and CVD mortality (1.14 [1.07-1.21]), which persisted after adjustment for age, sex, dialysis vintage, diabetes, and baseline CVD (1.12 [1.05-1.19] and 1.11 [1.02-1.19], all-cause and CVD mortality, respectively).
In long-term normoalbuminemic Japanese hemodialysis patients, with low prevalence of inflammation, OPG levels were strongly linked with both arterial stiffness and worse outcome.

DOI： 10.1007/s00198-010-1377-0

Web of Science

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER LONDON LTD  

Postmenopausal hemodialysis patients are at risk of complications related to renal mineral and bone disorder, and postmenopausal osteoporosis. In 112 postmenopausal hemodialysis patients, free estrogen index was positively correlated with bone mineral density (BMD) Z-score and the annual percent change of BMD in multiple regression analysis. Endogenous estrogen may prevent bone loss in postmenopausal hemodialysis patients throughout life.
Women on dialysis are not only at risk of developing mineral and bone disorder, but also suffer from postmenopausal osteoporosis. We assessed the effect of sex hormones on bone metabolism in postmenopausal hemodialysis patients.
We enrolled 112 postmenopausal hemodialysis patients with a mean age of 68.4 +/- 10.4 years. We measured the serum levels of estradiol, testosterone, sex hormone-binding globulin (SHBG), and intact parathyroid hormone (intact-PTH), as well as bone metabolism parameters and radial bone mineral density (BMD). The free estrogen index (FEI) was calculated from the estradiol and SHBG values. After conventional dialysis was performed for 12 months, BMD was measured again and the annual percent change was calculated. Estradiol and SHBG were also measured in 25 postmenopausal women without chronic kidney disease.
Estradiol levels were higher in the hemodialysis patients than in the postmenopausal women without chronic kidney disease. In patients with relatively normal bone turnover (intact-PTH: from 150 to 300 pg/ml), the FEI showed a positive correlation with the BMD Z-score. The annual percent change of BMD showed a positive correlation with the FEI according to multiple regression analysis.
Endogenous estrogen may prevent bone loss in postmenopausal hemodialysis patients throughout life.

DOI： 10.1007/s00198-010-1350-y

Web of Science

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Ghrelin abnormalities contribute to anorexia, inflammation, and cardiovascular risk in hemodialysis patients, leading to worse outcome. However, ghrelin levels are influenced by the nutritional status of the individual. We hypothesized that the consequences of ghrelin alterations in hemodialysis patients are context sensitive and dependent on the presence of protein-energy wasting (PEW). In this cross-sectional study of 217 prevalent hemodialysis patients followed for 31 months, we measured ghrelin, leptin, PEW (subjective global assessment), and C-reactive protein (an index of inflammation). Compared to patients in the middle and upper tertile of ghrelin levels, those in the lowest tertile were older, had higher leptin levels and body mass index, and presented an increased mortality risk that persisted after adjustment for age, gender, and dialysis vintage. This risk was lost after correction for comorbidities. Patients with PEW and low ghrelin values had abnormally high C-reactive protein and leptin by multivariate analysis of variance, and the highest mortality risk compared to non-PEW with high ghrelin from all-cause and cardiovascular-related mortality (adjusted hazard ratios of 3.34 and 3.54, respectively). Low ghrelin values in protein-energy wasted hemodialysis patients were linked to a markedly increased cardiovascular mortality risk. Thus, since these patients were more anorectic, our results provide a clinical scenario where ghrelin therapies may be particularly useful. Kidney International (2011) 79, 749- 756; doi: 10.1038/ki.2010.487; published online 22 December 2010

DOI： 10.1038/ki.2010.487

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/ndt/gfq697

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

Background: A low level of intact parathyroid hormone (PTH) is an indicator of adynamic bone disease in hemodialysis patients, and is associated with a significant increase of all-cause mortality. Thus, effective treatment for adynamic bone disease is required. We previously investigated the effect of vitamin K-2 on adynamic bone disease. In this study, we assessed the efficacy of oral vitamin K-2 in a controlled trial. Methods: Forty hemodialysis patients with low intact PTH levels (&lt;100 pg/ml) were randomly divided into two groups, which were a vitamin K-2 group receiving oral menatetrenone (45 mg/day) for 1 year and a control group without vitamin K-2. Venous blood samples were collected at baseline and during the study for measurement of bone metabolism parameters. Results: Thirty-three patients completed follow-up. There was a significant increase of the serum intact osteocalcin level after 1 month of vitamin K-2 administration. Serum levels of intact PTH, bone alkaline phosphatase, and cross-linked N-terminal telopeptide of type I collagen increased significantly after 12 months in the vitamin K-2 group. The serum osteoprotegerin level was decreased after 12 months in the vitamin K-2 group, but the change was not significant. Conclusion: Vitamin K-2 therapy improves bone remodeling in hemodialysis patients with a low intact PTH level. Copyright (C) 2010 S. Karger AG, Basel

DOI： 10.1159/000319642

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

Objective: To estimate total numbers of undiagnosed carriers of hepatitis C virus (HCV) and hepatitis B virus (HBV) in Japan. Methods: Area- and age-specific prevalence of HCV as well as HBV was determined in the first-time blood donors [20-39 years (n = 2,429,364)] and examinees of periodical health check-ups [40-74 years (6,204,968 for HCV and 6,228,967 for HBV)] in Japan. Prevalence in adolescents [5-19 years (79,256 for HCV and 68,792 for HBV)] was determined in a single prefecture, and that of HCV in the elderly (6 75 years) was estimated by the exponential model. HBV infection was determined by the detection of hepatitis B surface antigen, and HCV infection by either the algorithm or assuming persistent infection in 70% of the individuals with antibody to HCV. Results: Of the total population of 127,285,653 in 2005, 807,903 (95% CI 679,886-974,292) were estimated to be infected with HCV at a carrier rate of 0.63%, and 903,145 (837,189-969,572) with HBV at that of 0.71%. Conclusion: Accurate estimation of undiagnosed HCV and HBV carriers in the general population would help to predict the future burden of liver disease, and take appropriate measures for improving healthcare. Copyright (C) 2011 S. Karger AG, Basel

DOI： 10.1159/000324525

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/ndt/gfq397

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

There have been few long-term prospective studies investigating the effect of cinacalcet on secondary hyperparathyroidism with or without nodular hyperplasia. We examined whether the effect of cinacalcet on secondary hyperparathyroidism differed between patients with or without nodular hyperplasia. Stable hemodialysis patients with secondary hyperparathyroidism resistant to conventional treatment received cinacalcet for 12 months. Based on ultrasonography findings, patients were divided into group S (gland &lt; 500 mm3 without nodular hyperplasia) and group L (gland &gt;= 500 mm3 with nodular hyperplasia). Serum levels of intact parathyroid hormone, bone-specific alkaline phosphatase, osteocalcin, and cross-linked N-terminal telopeptide of type 1 collagen were measured. Thirty-one patients completed the study. The changes of parameters from the baseline did not differ significantly between the two groups after 6 months. However, the percentage reduction of each parameter was significantly smaller in group L compared with group S after 12 months. Nodular hyperplasia is associated with resistance to cinacalcet therapy in patients on chronic dialysis with secondary hyperparathyroidism.

DOI： 10.1111/j.1744-9987.2010.00843.x

Web of Science

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC NEPHROLOGY  

Background and objectives: The soluble receptor of advanced glycation end products (sRAGE) may exert anti-inflammatory protective roles on the vasculature. In contrast, the RAGE ligand S100A12 (also known as EN-RAGE) contributes to inflammation and the development of atherosclerosis in animal models. Whether alterations at this level contribute to the increased mortality observed in patients on dialysis is currently unknown.
Design, setting, participants, & measurements: Prospective study including 184 prevalent hemodialysis patients and 50 healthy controls matched for age and gender. Plasma concentrations of S100A12 and sRAGE were studied in relation to risk profile and mortality after a median follow-up period of 41 months.
Results: S100A12 and sRAGE levels were significantly elevated in hemodialysis patients compared with healthy controls. S100A12 had a strong positive correlation with C-reactive protein and IL-6, whereas sRAGE negatively associated with C-reactive protein. S100A12, but not sRAGE, was independently and positively associated with clinical cardiovascular disease (CVD). During follow-up, 85 (33 cardiovascular-related) deaths occurred. Whereas sRAGE did not predict mortality, S100A12 was associated with both all-cause (per log(10) ng/ml hazard ratio [HR] 1.93, 95% confidence interval [CI] 1.18 to 3.15) and CVD-related (HR 3.23, 95% CI 1.48 to 7.01) mortality, even after adjustment for age, sex, vintage, and comorbidities. Further adjustment for inflammation made the predictive value of S100A12 disappear for all-cause mortality, but still persisted in CVD-related mortality.
Conclusions:,Circulating S100A12 and sRAGE are both elevated in hemodialysis patients. However, only S100A12 associates with mortality, partly explained by its links with inflammation. Clin J Am Soc Nephrol 5: 2213-2219, 2010. doi: 10.2215/CJN.03360410

DOI： 10.2215/CJN.03360410

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WICHTIG EDITORE  

Background/Aims: Darbepoetin alpha is effective for renal anemia when epoetin is insufficient. We previously reported that the dose conversion ratio from epoetin alpha to darbepoetin alpha was 1:350.5 after 24 weeks of follow-up. This study assessed the conversion ratio in stable Japanese hemodialysis patients after 52 weeks.
Methods: A total of 104 hemodialysis patients who were stable on intravenous epoetin alpha were switched to intravenous darbepoetin alpha according to the 1:200 rule. Then they were followed for 52 weeks to assess changes of hemoglobin and the darbepoetin alpha dose.
Results: Eighty-five patients completed the study. Their hemoglobin increased very rapidly during the first 8 weeks. The final conversion ratio was 1:286.6 at 52 weeks. Darbepoetin alpha showed similar efficacy in diabetics and non-diabetics. Patients switching from a high epoetin alpha dose (&gt;= 4500 IU/week) had a higher conversion ratio compared with those switching from a low dose (&lt;4500 IU/week).
Conclusions: The dose conversion ratio of 1:200 was unsuitable and led to a rapid increase of hemoglobin. A conversion ratio of 1:250 to 1:300 should be employed when switching from epoetin alpha to darbepoetin alpha in Japanese patients.

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1744-9987.2009.00702.x

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

Background/Aims: Several reports have indicated that the measurement of parathyroid gland size assists the management of patients with secondary hyperparathyroidism. This study examined whether parathyroid gland enlargement influenced the response of secondary hyperparathyroidism to cinacalcet. Methods: Clinically stable hemodialysis patients with secondary hyperparathyroidism that was resistant to conventional treatment received cinacalcet for 6 months. Based on the parathyroid gland size measured by ultrasonography, the patients were divided into group S (gland &lt; 500 mm(3)) and group L (gland &gt;= 500 mm(3)). Serum levels of intact parathyroid hormone (intact PTH), bone-specific alkaline phosphatase, osteocalcin, and cross-linked N-terminal telopeptide of type 1 collagen were measured over time. Results: Twenty-four patients completed the study. In group S, all markers of bone metabolism and intact PTH were significantly decreased after 3 months of cinacalcet treatment. In contrast, there were no significant changes of these parameters, except for intact PTH, after 3 months in group L. After 6 months of cinacalcet treatment, however, all of the markers of bone metabolism were significantly decreased in both groups. Conclusions: The response to cinacalcet differed between groups S and L. Thus, the presence of parathyroid enlargement (nodular hyperplasia) may delay the response of secondary hyperparathyroidism to cinacalcet. Copyright (C) 2009 S. Karger AG, Basel

DOI： 10.1159/000262301

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL PUBLISHING, INC  

Mortality from cardiovascular or cerebrovascular disease due to atherosclerosis is increased in patients on chronic hemodialysis. Monocyte chemoattractant protein-1 and its receptor, C-C chemokine receptor 2, play an important role in recruiting monocytes to atherosclerotic lesions. The relationship between atherosclerosis in hemodialysis patients and C-C chemokine receptor 2 expression is unknown. Fifty-six patients on chronic hemodialysis and 27 age- and sex-matched controls were enrolled. Serum levels of monocyte chemoattractant protein-1 and expression of C-C chemokine receptor 2 by circulating monocytes were determined. Atherosclerosis was evaluated from the carotid intima-media thickness and cardio-ankle vascular index. Serum levels of monocyte chemoattractant protein-1 and expression of C-C chemokine receptor 2 by monocytes were significantly higher in the hemodialysis patients than the controls. Multiple regression analysis showed a positive correlation between receptor expression and both indexes of atherosclerosis. C-C chemokine receptor 2 expression by circulating monocytes influences atherosclerosis in patients on chronic hemodialysis.

DOI： 10.1111/j.1744-9987.2009.00658.x

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DEC1 (BHLHB2/Stra13/Sharp2) - a basic helix-loop-helix transcription factor - is known to be involved in various biological phenomena including clock systems and metabolism. In the clock systems, Dec1 expression is dominantly up-regulated by CLOCK : BMAL1 heterodimer, and it exhibits circadian rhythm in the suprachiasmatic nucleus (SCN) - the central circadian pacemaker - and other peripheral tissues. Recent studies have shown that the strong circadian rhythmicity of Dec1 in the SCN was abolished by Clock mutation, whereas that in the liver was affected, but not abolished, by Clock mutation. Moreover, feeding conditions affected hepatic Dec1 expression, which indicates that Dec1 expression is closely linked with the metabolic functions of the liver. Among ligand-activated nuclear receptors examined, LXRα and LXRβ with T0901317 - agonist for LXR - were found to be potent enhancers for Dec1 promoter activity, and a higher expression level of LXRα protein was detected in the liver than in the kidney and heart. T0901317 increased the levels of endogenous Dec1 transcript in hepatoma cells. Chromatin immunoprecipitation assay indicated that LXRα bound to the Dec1 promoter, and an LXRα-binding site was identified. These observations indicate that hepatic DEC1 mediates the ligand-dependent LXR signal to regulate the expression of genes involved in the hepatic clock system and metabolism. © Journal compilation © 2009 by the Molecular Biology Society of Japan/Blackwell Publishing Ltd.

DOI： 10.1111/j.1365-2443.2008.01247.x

Scopus

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

Background/Aims: Peritoneal fibrosis is a serious complication of peritoneal dialysis (PD). It has been reported that administration of mizoribine, an effective immunosuppressant, ameliorated renal fibrosis in a rat model of unilateral ureteral obstruction. We therefore examined the effects of mizoribine in an experimental model of peritoneal fibrosis. Methods: 24 rats were given a daily intraperitoneal injection of chlorhexidine gluconate and ethanol dissolved in saline. The rats were divided into three groups (n = 8 per group) that received either vehicle or mizoribine at a dose of 2 or 8 mg/kg once a day. 28 days after the start of the treatments the rats were sacrificed and peritoneal tissue samples collected. Macrophage infiltration (ED1), myofibroblast accumulation (alpha-smooth muscle actin (SMA)) and expression of type III collagen, transforming growth factor (TGF)-beta and monocyte chemotactic protein-1 (MCP-1) were examined by immunohistochemistry. Results: Mizoribine significantly suppressed submesothelial zone thickening and reduced macrophage infiltration. Mizoribine also reduced collagen III+ area and decreased the number of alpha-SMA(+), TGF-beta(+) and MCP-1(+) cells. The magnitude of the changes observed was dose-dependent. Conclusion: The administration of mizoribine prevented the progression of peritoneal fibrosis in this rat model. Mizoribine may represent a novel therapy for peritoneal sclerosis in patients undergoing long-term PD. Copyright (C) 2009 S. Karger AG, Basel

DOI： 10.1159/000213896

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

Background/Aims: Darbepoetin alpha is an erythropoietic agent with a 3-fold longer elimination half-life than epoetin. The recommended conversion ratio from epoetin to darbepoetin alpha is 1: 200 (1 mu g of darbepoetin alpha = 200 IU of epoetin), but several observations have suggested that this ratio overestimates the required dose of darbepoetin alpha. This study assessed the actual conversion ratio for stable Japanese hemodialysis patients and investigated whether darbepoetin alpha promotes uniform erythropoiesis. Methods: A total of 104 hemodialysis patients who were stable on epoetin alpha therapy at Hakuai Clinic in Japan were switched to intravenous darbepoetin alpha according to the 1: 200 rule. They were followed for 24 weeks to assess changes of hemoglobin and the dose of darbepoetin alpha, as well as changes of the reticulocyte count. Results: One hundred patients completed the 24-week study and the final conversion ratio was 1:350.5. Darbepoetin alpha showed a similar effect in diabetics and nondiabetics. Data on the reticulocyte count demonstrated that darbepoetin alpha had a sustained effect on erythropoiesis. Conclusion: Darbepoetin alpha is effective for Japanese dialysis patients at a lower dose than expected. Copyright (C) 2008 S. Karger AG, Basel

DOI： 10.1159/000183843

Web of Science

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC MICROBIOLOGY  

DEC1 suppresses CLOCK/BMAL1-enhanced promoter activity, but its role in the circadian system of mammals remains unclear. Here we examined the effect of Dec1 overexpression or deficiency on circadian gene expression triggered with 50% serum. Overexpression of Dec1 delayed the phase of clock genes such as Dec1, Dec2, Per1, and Dbp that contain E boxes in their regulatory regions, whereas it had little effect on the circadian phase of Per2 and Cry1 carrying CACGTT E' boxes. In contrast, Dec1 deficiency advanced the phase of the E-box-containing clock genes but not that of the E'-box-containing clock genes. Accordingly, DEC1 showed strong binding and transrepression on the E box, but not on the E' box, in chromatin immunoprecipitation, electrophoretic mobility shift, and luciferase reporter assays. Dec1(-/-) mice showed behavioral rhythms with slightly but significantly longer circadian periods under conditions of constant darkness and faster reentrainment to a 6-h phase-advanced shift of a light-dark cycle. Knockdown of Dec2 with small interfering RNA advanced the phase of Dec1 and Dbp expression, and double knockdown of Dec1 and Dec2 had much stronger effects on the expression of the E-box-containing clock genes. These findings suggest that DEC1, along with DEC2, plays a role in the finer regulation and robustness of the molecular clock.

DOI： 10.1128/MCB.02168-07

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Background. Renal ischemia-reperfusion injury affects the long-term outcome of renal graft survival. Thiazolidinediones (TZDs), synthetic peroxisome proliferator-activated receptor (PPAR)-gamma ligands, have been shown to exert therapeutic effects upon renal ischemia-reperfusion injury far beyond their use as insulin sensitizers. It has also been reported that hepatocyte growth factor (HGF) has a beneficial effect on renal ischemia-reperfusion injury and that TZDs induce increased HGF mRNA expression and protein secretion. We investigated the effect of troglitazone, one of the TZDs, in a rat model of renal ischemia-reperfusion injury.
Methods. A 45-minute period of warm renal ischemia was induced by bilateral clamping at 37 degrees C with rats being sacrificed before the onset of ischemia and at 2, 4, 6, and 12 hr after reperfusion. The expression of PPAR-gamma was measured by reverse-transcriptase polymerase chain reaction (RT-PCR) and western blotting while the production of HGF was investigated by RT-PCR and immunohistochemistry. The effect of troglitazone treatment on the level of apoptosis was determined by staining for cleaved caspase-3 and single-stranded DNA (ssDNA).
Results. The numbers of cleaved caspase-3 and ssDNA positive cells were decreased in rats treated with troglitazone. The production of HGF mRNA and protein was most intense at 4 hr. The expression of PPAR-gamma and HGF was increased in the group treated with troglitazone compared with the control group.
Conclusions. Pretreatment of rats with the PPAR-gamma ligand troglitazone decreased apoptotic cell death in renal ischemia-reperfusion injury as a result of the induction of HGF.

DOI： 10.1097/01.tp.0000269614.21367.3f

Web of Science

記述言語：日本語   掲載種別：（MISC）総説・解説（学術雑誌）  

J-GLOBAL

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPANESE BIOCHEMICAL SOC  

To elucidate the food-entrainable oscillatory mechanism of peripheral clock systems, we examined the effect of fasting on circadian expression of clock genes including Dec1 and Dec2 in mice. Withholding of food for 2 days had these effects: the expression level of Dec1 mRNA decreased in all tissues examined, although Per1 mRNA level markedly increased; Per2 expression was reduced in the liver and heart only 42-46 h after the start of fasting; and expression profiles of Dec2 and Bmal1 were altered only in the heart and in the liver, respectively, whereas Rev-erb alpha mRNA levels did not change significantly. Re-feeding after 36-h starvation erased, at least in part, the effect of fasting on Dec1, Dec2, Per1, Per2, and Bmal1 within several hours, and restriction feeding shifted the phase of expression profiles of all examined clock genes including Dec1 and Dec2. These findings indicate that short-term fasting and re-feeding modulate the circadian rhythms of clock genes to different extents in peripheral tissues, and suggest that the expression of Dec1, Per1, and some other clock genes was closely linked with the metabolic activity of these tissues.

DOI： 10.1093/jb/mvj165

Web of Science

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background. It is important to observe the flow pattern of dialysate when evaluating dialyzer function and developing the most appropriate design. We investigated dialysate flow through two polysulfone membrane dialyzers (TS-UL [Toray Medical] and APS-S [Asahi Medical]) by computed tomography (CT), with barium sulfate as the contrast medium. We also performed a clinical comparison of these two dialyzers. Methods. For the in vitro experiment, after confirming the steady-state flow of mock blood (xanthan gum solution
200 ml/min) and dialysate (500 ml/min), fresh dialysate, containing 5% (w/v) barium sulfate was perfused, and longitudinal CT scans of the dialyzer were obtained. Then the concentration of barium sulfate was measured (in Hounsfield units) in three fixed regions of interest. For the in vivo experiment, 12 patients on stable hemodialysis who had been using the APS-S for more than 1 month were switched to the TS-UL for 1 month and changes in various parameters were assessed. Results. The distribution of dialysate was homogeneous on CT scans of the TS-UL, but not on scans of the APS-S. The dialysate concentration curves for the three regions of interest were similar with the TS-UL, but not with the APS-S. Clearance of urea nitrogen and albumin loss were both significantly higher with the TS-UL than with the APS-S. The decrease in alpha 1-microglobulin was larger with the TS-UL than with the APS-S, but not significantly. Conclusions. Clearance of substances over a wide range of molecular weights was higher with the TS-UL than with the APS-S, and differences in the design of the dialysate compartment may have been involved in this feature. © 2006 Japanese Society of Nephrology.

DOI： 10.1007/s10157-006-0431-x

Scopus

PubMed

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00198-005-0047-0

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Endocrine Society  

Context: Adiponectin is a hormone secreted by adipocytes that acts as an antidiabetic adipokine. Adiponectin exists as multimers in plasma, and high molecular weight (HMW) adiponectin is particularly thought to be the active form of the protein. Objective: The aim of the study was to assess whether decreased total and HMW adiponectin are independent risk factors for the development of type 2 diabetes. Design: Study subjects were Japanese-Americans enrolled in the Hawaii-Los Angeles-Hiroshima study between 1992 and 2002. Duration of follow-up was an average of 5.4 yr. Participants: We investigated 321 men and 445 women who were nondiabetic Japanese-Americans. Glucose tolerance was evaluated according to 1997 American Diabetes Association criteria, and 112 subjects developed type 2 diabetes during the follow-up period. Main Outcome Measure: The influence of baseline total and HMW adiponectin on the development of type 2 diabetes was the main outcome measure. Results: Subjects who developed type 2 diabetes had significantly decreased plasma total and HMW adiponectin compared with those who did not develop the disease (P &lt
0.001, respectively). In a Cox proportional hazards model, both decreased total and HMW adiponectin levels were independent risk factors for the progression to type 2 diabetes after adjusting for sex, age, body mass index, waist-to-hip ratio, homeostasis model assessment, and classification of 75-g glucose tolerance test (hazards ratio: total, 0.600, P = 0.018
HMW, 0.614, P = 0.001, respectively). Dividing tertiles of adiponectin, hazards ratios in the lowest vs. highest tertile were total, 1.787 (95% confidence interval, 1.006-3.173)
and HMW, 2.493 (95% confidence interval, 1.342-4.632), after similar adjustments. Conclusions: Decreased total adiponectin is an independent risk factor for the progression to type 2 diabetes in Japanese-Americans. Moreover, HMW adiponectin more closely associates with the progression to type 2 diabetes when compared with total adiponectin. Copyright © 2006 by The Endocrine Society.

DOI： 10.1210/jc.2006-1158

Scopus

PubMed

記述言語：日本語   掲載種別：（MISC）研究発表要旨（全国大会，その他学術会議）  

J-GLOBAL

記述言語：日本語   掲載種別：（MISC）研究発表要旨（全国大会，その他学術会議）  

J-GLOBAL

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

Background: Useful markers of bone resorption are needed for hemodialysis patients with renal osteodystrophy. This study investigated the use of a new immunoassay for cross-linked N-terminal telopeptide of type 1 collagen to assess bone changes in hemodialysis patients. Methods: Radial bone mineral density was examined in 178 hemodialysis patients at baseline and after 12 months. Serum levels of N-terminal telopeptide and other markers were measured. Results: The annual percent change of radial bone mineral density was negatively correlated with the levels of N-terminal telopeptide, intact osteocalcin, tartrate-resistant acid phosphatase, bone-specific alkaline phosphatase, and intact parathyroid hormone. The annual percent change of radial bone mineral density showed a stronger correlation with N-terminal telopeptide levels than with the other markers, except for intact parathyroid hormone. Also, intact parathyroid hormone and N-terminal telopeptide levels showed a stronger correlation than that of either tartrate-resistant acid phosphatase or cross-linked carboxyterminal telopeptide of type 1 collagen with intact parathyroid hormone. Conclusion: Serum N-terminal telopeptide may be the most useful bone resorption marker in renal osteodystrophy and its use combined with bone formation markers may improve the management of this condition. Copyright (C) 2005 S. Karger AG, Basel.

DOI： 10.1159/000083418

Web of Science

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING LTD  

Aims It has been reported that 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors increase bone mineral density (BMD) in vivo. We investigated the effect of HMG-CoA reductase inhibitors on BMD in patients with Type 2 diabetes mellitus.
Patients and methods We selected 122 patients with Type 2 diabetes, who were not taking active vitamin D preparations. Their mean age was 67.3 +/- 9.2 years. They were divided into a control group (n = 63) without HMG-CoA reductase inhibitor therapy and an HMG-CoA group (n = 59) who were treated with these drugs. The BMD of the distal one-third of the radius was measured by dual-energy X-ray adsorptiometry at baseline and after 2 years.
Results There were no significant differences between the control and HMG-CoA groups at baseline with respect to age, gender, body mass index, duration of diabetes, haemoglobin A(1c), fasting plasma glucose, adjusted calcium, serum phosphorus, alkaline phosphatase, albumin excretion rate and radial BMD. However, there was a significantly smaller annual decrease of the radial BMD in the HMG-CoA group. Multiple regression analysis with a forward elimination procedure revealed a positive correlation of the radial BMD Z-score with body mass index, while there was a negative correlation with alkaline phosphatase and albumin excretion rate. In addition, the annual rate of change of the radial BMD showed a positive correlation with HMG-CoA reductase inhibitor therapy.
Conclusions These findings suggest that HMG-CoA reductase inhibitors may prevent bone loss in patients with Type 2 diabetes.

DOI： 10.1111/j.1464-5491.2004.01292.x

Web of Science

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

In patients with adynamic bone disease, the bone contains few osteoblasts or osteoclasts and bone turnover is slow, so the risk of fracture is increased. The decrease of bone remodeling may also decrease the capacity of bone to buffer calcium, leading to an increase of the calcium x phosphate product and an increased risk of arterial calcification. Such findings emphasize that an effective treatment for adynamic bone disease is required. The present study investigated the influence of vitamin K-2 (menatetrenone) on hemodialysis patients with low serum parathyroid hormone levels by using bone metabolism markers.
The subjects were 32 hemodialysis patients (19 men and 13 women) aged from 2.7 to 76 years with an intact parathyroid hormone (PTH) level of less than 65 pg/ml and an intact osteocalcin level below 20 ng/ml. All patients received oral menatetrenone therapy (45 mg/day) for 12 months. To obtain control data on bone metabolism markers in hemodialysis patients with normal bone turnover, we selected 50 patients who had intact PTH levels within the range that maintains relatively normal bone turnover, that is, from 120 to 250 pg/ml.
The baseline levels of all bone metabolism markers were significantly lower in our patients than in the normal PTH control group. There was a significant increase of gamma-carboxyglutamate (Gla) osteocalcin, bone alkaline phosphatase (B-ALP), tartrate-resistant acid phosphatase (TRACP), and cross-linked N-terminal telopeptide of type 1 collagen (NTx) levels after vitamin K-2 administration. Type 1 procollagen carboxyterminal propeptide (P1CP) and intact osteocalcin both showed a significant increase after 12 months of treatment. Although there was no significant change of the alkaline phosphatase (ALP) level during the 12 months before the start of vitamin K-2 therapy, there was a significant increase of alkaline phosphatase after vitamin K-2 administration. Adjusted calcium, serum phosphate, and intact PTH showed no significant changes throughout the study.
These changes of bone metabolism markers suggested that vitamin K-2 therapy can improve bone remodeling in hemodialysis patients with low serum PTH levels. (C) 2004 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bone.2003.11.016

Web of Science

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

Objective High-resolution B-mode ultrasonography has been widely used for the noninvasive assessment of atherosclerosis in hemodialysis patients. But, there are two major methods of carotid ultrasonography: one including plaque and the other excluding plaque.
Methods The subjects were 112 hemodialysis patients (58 men and 54 women) with a mean age of 55.8 +/- 13.0 years. The maximum intima-media thickness (IMT) of the carotid artery (including plaque) was measured as an index of arterial wall thickening and atheroma formation, while the mean IMT (without plaque) was measured as an index of arterial wall thickening. In addition the value of (maximum-mean) IMT was calculated as an index of atheroma formation. Therefore, the independent risk factors associated with the maximum IMT, mean IMT, and (maximum-mean) IMT were investigated by stepwise multiple regression analysis.
Results The independent risk factors associated with the maximum IMT were age, diabetes mellitus, smoking, and intact parathyroid hormone (PTH) (R=0.569, p&lt;0.0001), while factors associated with the mean IMT were age, hypertension, dyslipidemia, intact PTH, and lipoprotein (a) (R=0.602, p&lt;0.0001). The independent risk factors associated with the (maximum-mean) IMT were age, diabetes mellitus, smoking, and intact PTH (R=0.515, p&lt;0.0001).
Conclusion These findings suggest that risk factors for the maximum IMT and mean IMT are somewhat different in hemodialysis patients.

Web of Science

記述言語：英語   掲載種別：（MISC）研究発表要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00198-002-1361-4

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WICHTIG EDITORE  

Adynamic bone disease (ABD) has attracted attention as the most frequent type of renal osteodystrophy, but there are few reports about the bone mineral density (BMD) in ABD patients. This study investigated the BMD in hemodialysis patients with ABD and with relatively normal bone turnover. We measured the BMD of the distal one-third of the radius by dual-energy X-ray adsorptiometry,
In the ABD group (intact PTH&lt;65pg/ml, intact osteocalcin&lt;30ng/ml), there were 19 men and 17 women with a mean age of 56.4+/-12.0 years. In the relatively normal bone turnover group (intact PTH: 120-250pg/ml), there were 24 men and 16 women with a mean age of 57.1+/-14.7 years. Although there were no significant differences between the two groups with respect to age, gender, and duration of hemodialysis, a significant increase of the BMD and the calcium x phosphate product was observed in the ABD group (radial BMD: 0.648+/-0.137 g/cm(2) versus 0.572+/-0.132 g/cm(2), calcium x phosphate product: 57.53+/-14.92 mg(2)/dl(2) versus 49.76+/-12.13 mg(2)/dl(2)).
These findings suggest that an increase in radial BMD may not be a useful marker of the improvement in bone lesions in ABD patients.

Web of Science

記述言語：日本語  

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記述言語：日本語   著書種別：学術書

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記述言語：日本語   著書種別：学術書

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開催年月日： 2024年9月

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記述言語：日本語   会議種別：ポスター発表  

記述言語：日本語  

開催地：Melboirne  

記述言語：日本語   会議種別：ポスター発表  

記述言語：日本語   会議種別：ポスター発表  

開催地：新潟  

記述言語：日本語   会議種別：ポスター発表  

開催地：新潟  

記述言語：日本語   会議種別：口頭（一般）  

開催地：東京  

記述言語：日本語   会議種別：口頭（一般）  

開催地：神戸  

記述言語：日本語   会議種別：口頭（一般）  

開催地：神戸  

記述言語：日本語   会議種別：ポスター発表  

開催地：日本 東京  

記述言語：日本語   会議種別：ポスター発表  

開催地：日本 東京  

記述言語：日本語   会議種別：ポスター発表  

開催地：日本 東京  

記述言語：日本語   会議種別：ポスター発表  

開催地：日本 東京  

開催年月日： 2017年11月

記述言語：英語  

開催年月日： 2017年11月

記述言語：英語  

開催年月日： 2017年11月

記述言語：英語  

開催年月日： 2017年11月

記述言語：英語  

記述言語：日本語   会議種別：ポスター発表  

開催地：アメリカ ニューオリンズ  

記述言語：日本語   会議種別：ポスター発表  

開催地：アメリカ ニューオリンズ  

記述言語：日本語   会議種別：ポスター発表  

開催地：パシフィコ横浜  

記述言語：日本語   会議種別：ポスター発表  

開催地：パシフィコ横浜  

記述言語：日本語   会議種別：口頭（一般）  

開催地：仙台国際センター  

記述言語：日本語   会議種別：ポスター発表  

開催地：仙台国際センター  

記述言語：英語  

開催地：広州 中国