Valsartan improves L-NAME-exacerbated cardiac fibrosis with TGF-β inhibition and apoptosis induction in spontaneously hypertensive rats

被引:29
作者
Akashiba, Akira [1 ]
Ono, Hidehiko [1 ]
Ono, Yuko [1 ]
Ishimitsu, Toshihiko [1 ]
Matsuoka, Hiroaki [1 ]
机构
[1] Dokkyo Med Univ, Dept Hypertens & Cardiorenal Med, Mibu, Tochigi 3210293, Japan
关键词
Hypertension; Nitric oxide; Cardiac fibrosis; Apoptosis; Caspase-3; Tissue transforming growth factor-beta; Valsartan; Angiotensin II receptor blocker;
D O I
10.1016/j.jjcc.2008.07.018
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
This study was designed to investigate whether chronic angiotensin II type 1 receptor blockade inhibits ventricular interstitial fibrosis with the induction of programmed cell death (apoptosis) in prolonged nitric oxide synthase (NOS) inhibition using N-G-nitro-L-arginine methyl ester (L-NAME) in spontaneously hypertensive rats (SHR). Four groups of 20-week-old male SHR were studied for 3 weeks: the control group; the L-NAME group given 80 mg/L L-NAME in drinking water; and the groups given 1 or 30 mg/(kg day) of valsartan, respectively, with L-NAME. The L-NAME group showed marked cardiac tissue injuries with elevated blood pressure such as interstitial fibrosis, intimal thickening of small arteries, and myocardial necrosis. Caspase-3, an apoptosis inducer, immunoreactivity was increased in interstitial cells, and the tissue RNA expression of transforming growth factor-beta(1) (TGF-beta(1)) was also increased in the L-NAME group. Low-dose valsartan treatment did not affect blood pressure or cardiac weight but alleviated the L-NAME-induced interstitial fibrosis with increased mRNA level of caspase-3 in interstitial fibroblasts. High-dose valsartan significantly lowered blood pressure and decreased the mRNA levels of caspase-3 and TGF-beta(1). These data suggest that low-dose valsartan inhibits interstitial fibrosis by promoting apoptosis of the fibroblasts without blood pressure changes, which may provide the TGF-beta(1) inhibition in the development of interstitial fibrosis in severe hypertension rat model. (C) 2008 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved.
引用
收藏
页码:239 / 246
页数:8
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