Rosuvastatin prevents pressure overload-induced myocardial hypertrophy via inactivation of the Akt, ERK1/2 and GATA4 signaling pathways in rats

Pressure overload-induced myocardial hypertrophy is associated with a poor prognosis in humans and contributes to the development of cardiac arrhythmias, diastolic dysfunction and ultimate congestive heart failure. 3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, also known as statins, have been previously shown to induce regression of myocardial hypertrophy in aortic banding models. However, there is limited knowledge regarding the underlying molecular mechanisms. Therefore, we hypothesized that the myocardial hypertrophy-related signaling pathways protein kinase B (Akt), extracellular signal-regulated kinases 1 or 2 (ERK1/2) and GATA binding protein 4 (GATA4) activation pathways constitute targets of rosuvastatin (RSV). Therefore, the above-mentioned activation pathways were hypothesized to be involved in the regression of pressure overload-induced myocardial hypertrophy treated by RSV. Twenty-eight Wistar rats were randomly allocated into 4 groups: the sham operation-vehicle (SH-V), abdominal aortic constriction-vehicle (AAC-V), abdominal aortic constriction-RSV 10 mg/kg/day (AAC-LO) and the abdominal aortic constriction-RSV 20 mg/kg/day (AAC-HI) group. Following the establishment of the abdominal aorta constriction model, we investigated the effect of RSV, a new hydrophilic statin, on abdominal aortic constriction-induced myocardial hypertrophy as well as the underlying intercellular signaling pathways after 5 days and 4 weeks of drug intervention. Moreover, echocardiographic features and the left ventricular weight to final body weight ratio (LVW/BW) were determined. Cross-sectional areas (CSAs) of cardiomyocytes were assessed by hematoxylin and eosin (H&E) staining. Atrial natriuretic factor (ANF), beta-myosin heavy chain (beta-MHC) and peroxisome proliferator-activated receptor alpha (PPAR alpha) messenger RNA (mRNA) expression was assessed using RT-PCR. The phosphorylation of Akt, ERK1/2 and GATA4 were also examined using western blot analysis. Our results showed that RSV significantly attenuates pressure overload-induced myocardial hypertrophy by preventing myocardial hypertrophy-related activation of Akt, ERK1/2 and GATA4 signaling pathways.