The nonpeptide AVE0991 attenuates myocardial hypertrophy as induced by angiotensin II through downregulation of transforming growth factor-beta1/Smad2 expression.

The nonpeptide AVE0991 is expected to be a putative new drug for cardiovascular diseases. However, the mechanisms for the cardioprotective actions of AVE0991 are still not fully understood. We planned to determine whether AVE0991 attenuates the angiotensin II (AngII)-induced myocardial hypertrophy and whether these AVE0991 effects involved transforming growth factor beta1 (TGF-beta1) and Smad2. A rat model of neonatal myocardial hypertrophy was induced by AngII. The AngII group significantly increased in protein content, surface area, and [(3)H]leucine incorporation efficiency by cardiomyocytes, compared to those of the control group (P < 0.01). The AngII group also had elevated TGF-beta1 and Smad2 expression (P < 0.01). These AngII-induced changes were significantly attenuated by AVE0991 in a dose-dependent manner. In our study, these actions of AngII (10(-6) mol/l) were significantly inhibited by both concentrations of AVE0991 (10(-5) mol/l and 10(-7) mol/l). Moreover, the high AVE0991 group had significantly better inhibition of myocardial hypertrophy than the low AVE0991 group. Meanwhile, the beneficial effects of AVE0991 were completely abolished when the cardiomyocytes were pretreated with Ang-(1-7) receptor antagonist A-779 (10(-6) mol/l). These results suggested that AVE0991 prevented AngII-inducing myocardial hypertrophy in a dose-dependent fashion, a process that may be associated with the inhibition of TGF-beta1/Smad2 signaling.