Simvastatin activates the PPARγ-dependent pathway to prevent left ventricular hypertrophy associated with inhibition of RhoA signaling.

Left ventricular hypertrophy is an independent risk factor for major adverse cardiovascular events. Statins have positive effects on this condition; however, the mechanisms are incompletely understood. In this study, we examined whether the effect of simvastatin on left ventricular hypertrophy can be mediated with the peroxisome proliferator-activated receptor (PPAR)γ-dependent pathway in rabbits with nonischemic heart failure (HF). We induced aortic insufficiency and constriction in 48 rabbits and divided them equally into control, HF, and HF with simvastatin therapy (HF-SIM) groups. The HF-SIM group was given 10 mg/kg/d of simvastatin. We echocardiographically measured baseline and 8-week cardiac structure and function, and we used Western blot, polymerase chain reaction, and electrophoretic analytic techniques to evaluate messenger RNA expression and protein expression and activity. In comparison with the HF group, the HF-SIM rabbits had an increased ejection fraction and decreased left ventricular mass index, interventricular septal thickness, ventricular posterior-wall thickness, and collagen volume fraction. Moreover, the messenger RNA and protein expression of PPARγ in the HF-SIM rabbits were significantly higher than those in the HF rabbits; and the activity and expression of nuclear factor-κB subunit p65, RhoA, and Rho GTPase were significantly lower. Our results indicate that simvastatin therapy attenuates the PPARγ-dependent pathway in association with the inhibition of RhoA and Rho GTPase signaling to inhibit nuclear factor-κB activation, thus preventing the development of left ventricular hypertrophy and fibrosis in rabbits with nonischemic heart failure.