Metformin attenuates cardiomyocyte hypertrophy through mitochondria: reciprocal interaction between AMPK and angiotensin II type 1 receptor

Abstract

Activation of AMP‐kinase (AMPK) reduces cardiac hypertrophy although molecular mechanisms underlying this effect remain unclear. We examined the role of the AMPK/eNOS/p53 pathway in the antihypertrophic action of metformin (Met) in cell hypertrophy induced by angiotensin II (AngII). H9c2 cardioblasts were treated with AngII for 24h in the presence of the AMPK agonist, Met, the AngII type 1 receptor (AT1R) blocker, lasartan, the pan‐NOS inhibitor, Nω‐nitro‐L‐arginine methyl ester (L‐NAME) or the SIRT1 inhibitor, splitomicin. AngII increased AT1R expression and AMPK phosphorylation by 38% (P<0.05) and 20% (P>;0.05), respectively, compared to control. Upregulation of AT1R was prevented by lasartan that was associated with further phosphorylation of AMPK by 54% (P<0.05). Likewise, Met increased AMPK phosphorylation by 99% (P<0.01) and reduced AT1R levels by 30% (P<0.03) in the presence of AngII. Met also enhanced p‐eNOS levels by 3.3 folds (P<0.01) and prevented AngII‐induced upregulation of p53. Both L‐NAME and splitomicin decreased AT1R expression in AngII‐treated cells. Beneficial effects of Met converged on mitochondria that exhibited high membrane potential (Δψm). We concluded that antihypertrophic effects of Met were associated with the AT1R downregulation preventing mitochondrial dysfunction through the eNOS/SIRT1/p53 pathway. Supported by the grant SC1HL118669 from NHLBI NIH.