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

Abstract

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-ß(1) (TGF-ß(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-ß(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-ß(1) inhibition in the development of interstitial fibrosis in severe hypertension rat model.

Reversion of left ventricle remodeling in spontaneously hypertensive rats by valsartan is associated with the inhibition of caspase-3, -8 and -9 activities

“…The caspase is involved in apoptosis, and therefore it was used in the present study as a marker of apoptosis. Previous studies showed that valsartan, an angiotensin II antagonist, could exert an effect on apoptosis and left ventricular remodeling (10,14,15). However, the underlying mechanisms remain unclear.…”

Candesartan antagonizes pressure overload-evoked cardiac remodeling through Smad7 gene-dependent MMP-9 suppression

“…In our study, we proved that Candesartan significantly delayed the process of EMT by decreasing the expression of collagens and fibronectins. Plenty of studies suggested that excessive accumulation of newly formed ECM could be suppressed by ARBs in heart, lung, liver and kidney (Akashiba et al, 2008;Sukumaran et al, 2010), and the attenuated MMP activities might be the underlying mechanism, which was different from the various of ECM signaling molecules, such as Smads and PKC. Here we found that Smad7 upregulation was required for Candesartan induced MMP-9 suppression in pressure overload hearts.…”

Extracellular matrix remodeling in atrial fibrosis: Mechanisms and implications in atrial fibrillation

“…The ARB, valsartan reduced the degree of myocardial fibrosis in hypertensive rats [43]. Similarly, candesartan, which is another ARB, reduced interstitial fibrosis and AF duration in a canine model of AF [44].…”