論文 - 小山　雅之

Elevation of Fatty Acid-Binding Protein 4 Is Predisposed by Family History of Hypertension and Contributes to Blood Pressure Elevation

Hideki Ota, Masato Furuhashi, Shutaro Ishimura, Masayuki Koyama, Yusuke Okazaki, Tomohiro Mita, Takahiro Fuseya, Tomohisa Yamashita, Marenao Tanaka, Hideaki Yoshida, Kazuaki Shimamoto, Tetsuji Miura

AMERICAN JOURNAL OF HYPERTENSION ( OXFORD UNIV PRESS )  25 ( 10 ) 1124 - 1130  2012年10月  [査読有り]  [国際誌]

　概要を見る

BACKGROUND Fatty acid-binding protein 4 (FABP4/A-FABP/aP2), a lipid chaperone, is expressed in both adipocytes and macrophages. Recent studies have shown secretion of FABP4 from adipocytes and association of elevated serum FABP4 level with obesity, insulin resistance, and atherosclerosis. However, little is known about the role of FABP4 in essential hypertension. METHODS We first examined serum FABP4 concentrations in 18 normotensives (NT) and 30 nontreated essential hypertensives (EHT). The EHT were divided into 18 insulin-sensitive EHT (EHT-S) and 12 insulin-resistant EHT (EHT-R) based on their insulin-sensitivity index, the M value, determined by the hyperinsulinemic euglycemic clamp technique. In the second study, we determined FABP4 levels in 30 young NT men with or without a family history of hypertension (FH+ and FH-, respectively; n = 15 each). RESULTS Serum FABP4 level was significantly higher in the EHT-R than in the NT, whereas elevation of FABP4 level in the EHT-S was not statistically significant. FABP4 level was positively correlated with age, body mass index (BMI), blood pressure, and triglycerides and negatively correlated with the M value. FABP4 level was an independent predictor of mean arterial pressure after adjustment of age, gender, and adiposity. The FH+ group had a significantly lower level of M value and higher level of FABP4 than did the FH(-)group, and FABP4 concentration was an independent determinant of the M value. CONCLUSIONS FABP4 contributes to blood pressure elevation and atherogenic metabolic phenotype in hypertensives, and the elevation of FABP4 is predisposed by a family history of hypertension.

DOI PubMed

Angiotensin II receptor activation in youth triggers persistent insulin resistance and hypertension-a legacy effect?

Nobuhiko Togashi, Takuto Maeda, Hideaki Yoshida, Masayuki Koyama, Marenao Tanaka, Masato Furuhashi, Kazuaki Shimamoto, Tetsuji Miura

HYPERTENSION RESEARCH ( NATURE PUBLISHING GROUP )  35 ( 3 ) 334 - 340  2012年03月  [査読有り]  [国際誌]

　概要を見る

Although the involvement of angiotensin II (Ang II) in insulin resistance and hypertension has been established, the temporal relationships between Ang II receptor activation and changes in insulin sensitivity and blood pressure are not clear. To better understand this issue, we infused rats with Ang II (200 ng kg(-1) min(-1)) or vehicle for 4 weeks and assessed the residual effects after the discontinuation of the infusion on blood pressure, insulin sensitivity and tissue parameters of inflammation. Four weeks after the discontinuation of the Ang II infusion, the blood pressure was higher by 12.8mmHg, and insulin sensitivity as determined by a euglycemic hyperinsulinemic glucose clamp was reduced (glucose infusion rate: 11.1+/-0.7 vs. 17.6+/-0.5mg kg(-1) min(-1)) in the Ang II-treated group compared with controls. The persistent hypertension and insulin resistance were associated with greater than two-fold increases in macrophage chemoattractant protein-1, tumor necrosis factor-alpha and thiobarbituric acid-reactive substrates in the soleus muscle. Furthermore, total and activated forms of Rac-1, a regulatory subunit of the NADPH oxidase complex, were increased by 144 +/- 14% and 277 +/- 82%, respectively, in the skeletal muscle of Ang II-treated rats. These residual effects after Ang II infusion were all attenuated by the co-administration of tempol, a free radical scavenger, or candesartan with Ang II. The effects of candesartan were not mimicked by hydralazine at an equidepressant dose. These findings suggest that Ang II receptor activation in youth triggers the upregulation of inflammatory cytokines and the production of reactive oxygen species, thereby inducing later insulin resistance and hypertension. Hypertension Research (2012) 35, 334-340; doi: 10.1038/hr.2011.206; published online 1 December 2011

DOI PubMed

Deterioration of Renal Function by Chronic Heart Failure is Associated with Congestion and Oxidative Stress in the Tubulointerstitium

Marenao Tanaka, Hideaki Yoshida, Masato Furuhashi, Nobuhiko Togashi, Masayuki Koyama, Satoshi Yamamoto, Tomohisa Yamashita, Yusuke Okazaki, Shutaro Ishimura, Hideki Ota, Tadashi Hasegawa, Tetsuji Miura

INTERNAL MEDICINE ( JAPAN SOC INTERNAL MEDICINE )  50 ( 23 ) 2877 - 2887  2011年  [査読有り]  [国内誌]

　概要を見る

Objective We examined the hypothesis that renal congestion is responsible for the decline in renal function in patients with heart failure (HF) via tubulointerstitial inflammation. Methods First, in a longitudinal study, we retrospectively examined the relationship between cardiac functions and the decline of renal function during a period of 6.4 +/- 3.2 years in 20 patients who had a left ventricular ejection fraction of <40% and an estimated glomerular filtration ratio (eGFR) of <60 mL/min/1.73 m(2). Second, we compared the renal histology in autopsy cases of HF-induced renal dysfunction (HF-RD), cases of nephrosclerosis (NSC) and cases of neither RD nor HF (controls) in a cross-sectional study. Third, we retrospectively examined renal function in HF patients with predominantly right, but not left, ventricular dysfunction. Results eGFR decreased at 9.4 +/- 4.6%/year in the cohort of the longitudinal study. The rate of eGFR decline was correlated with blood pressure and with diameter of the inferior vena cava (IVCd) (r=0.5) measured at the initial work-up. Multivariate analysis indicated that the IVCd is an independent determinant of decline of eGFR in HF. In the cross-sectional study, fibrosis, Rac1 expression, protein nitrosylation, and number of CD68-positive cells were increased in the tubulointerstitium in both cases of HF-RD and NSC. Peritubular capillaries in HF-RD were dilated by 35% without any change in density compared with those in the controls. In right sided HF, the reduction of IVCd after treatment was associated with improvement of eGFR. Conclusion Venous congestion may contribute to HF-induced deterioration of renal function by augmenting oxidative stress-mediated inflammation in the tubulointerstitium.

DOI PubMed

Endoplasmic reticulum stress-induced chronic inflammation and cardiovascular disease

Furuhashi, M., Ishimura, S., Koyama, M.

Respiration and Circulation   59 ( 9 )  2011年