Effects of metformin on pressure overload-induced cardiac hypertrophy in rats

AIM: To study the effects of metformin on the pressure overload-induced cardiac hypertrophy in rats. METHODS: Transverse aortic constriction (TAC) model of rat was made through laparotomy. One week after TAC surgery, the rats were randomly divided into 5 groups (n=8 in each group) and were administered with the corresponding drugs orally every day for 8 weeks: sham group (sham surgery, administered with 2 mL distilled water); TAC group (TAC rats, administered with 2 mL distilled water); metformin (MET) group (TAC rats, administered with MET at dose of 300 mg·kg^-1·d^-1); MN group [TAC rats, administered with MET at dose of 300 mg·kg^-1·d^-1 plus NOS inhibitor, N^G-nitro-L-arginine methyl ester (L-NAME) 50 mg·kg^-1·d^-1] and L-NAME group (TAC rats, administered with L-NAME at dose of 50 mg·kg^-1·d^-1). After treated for 8 weeks, the echocardiography, hemodynamics, the ratio of heart weight to body weight (HW/BW) and histological examination of the heart were performed. The levels of myocardial AMP-activated protein kinase subunit α (AMPKα), p-AMPKα Thr172, endothelial nitric oxide synthase (eNOS) and p-eNOS Ser1177 were detected by Western blotting. Plasma and myocardial nitric oxide (NO) were detected biochemically. RESULTS: After 8 weeks treatment, the wall thickness of left ventricle, the heart weight/body weight ratio (HW/BW), and the left ventricular myocardial perivascular fibrosis and myocardial interstitial fibrosis of the animals in TAC group were significantly increased as compared to those in sham rats. Treatment with MET for 8 weeks significantly attenuated left ventricular hypertrophy and improved cardiac function in TAC rats. These effects of MET were mostly abolished by L-NAME. Molecular biology and biochemical testing revealed that the levels of left ventricular myocardial p-AMPKα Thr172 and p-eNOS Ser1177, as well as the levels of myocardial and serum NO were significantly increased in MET group. CONCLUSION: Long-term MET treatment significantly inhibits the cardiac hypertrophy and the myocardial fibrosis and improves the cardiac functions in pressure-overload rats. The anti-hypertrophic effects of MET may be mediated via activation of AMPK-eNOS signaling pathway.