Sub-depressor dose of angiotensin type-1 receptor blocker inhibits transforming growth factor-beta-mediated perivascular fibrosis in hypertensive rat hearts.

Abstract

Recently, we have shown that pressure overload transiently induces transforming growth factor-beta-mediated fibroblast proliferation and reactive myocardial fibrosis that extends from the perivascular space. However, the upper stream event of transforming growth factor-beta induction has remained unknown. Thus, we sought to determine whether angiotensin II mediates the fibrotic process in pressure-overloaded hearts. Male Wistar rats were administered orally everyday 0.1 mg/kg per day of candesartan, an angiotensin type-1 receptor blocker, or the vehicle from Day 7, and underwent a suprarenal aortic constriction (AC) at Day 0. This dose was the maximum dose of candesartan that does not induce the depressor effect in AC rats. In AC+ vehicle (control) rats, pressure overload induced myocardial transforming growth factor-beta expression and perivascular fibroblast proliferation at Day 3 and thereafter left ventricular hypertrophy associated with cardiomyocyte hypertrophy and perivascular fibrosis. AC+ candesartan rats showed suppressed transforming growth factor-beta expression and reduced number of proliferating fibroblasts, while not changing arterial pressure. Furthermore, perivascular fibrosis, but not myocyte hypertrophy, was significantly inhibited associated with reduced collagen mRNA expression. In conclusion, angiotensin II may play a role in reactive myocardial fibrosis in pressure-overloaded hearts, through the mechanism independent of hemodynamic change.