Metformin Protects against H2O2-Induced Cardiomyocyte Injury by Inhibiting the miR-1a-3p/GRP94 Pathway

Abstract Ischemia-reperfusion (I/R) injury is a major side effect of the reperfusion treatment of the ischemic heart. Few therapies are available for the effective prevention of this injury caused by the oxidative stress-induced cardiomyocytes apoptosis. Metformin was shown to have a potential cardiac protective effect and ability to reduce cardiac events, but the exact mechanism remains unclear. Here, we aimed to confirm and investigate the mechanisms underlying potential metformin activity against I/R injury in response to oxidative stress. We determined that the expression of miR-1a-3p was significantly increased in neonatal rat ventricular cells (NRVCs) which were exposed to H 2 O 2 in vitro and in the hearts of mice which underwent the I/R injury. MiR-1a-3p was shown to target the 3′-untranslated region (3′-UTR) of GRP94, which results in the accumulation of un/misfolded proteins, leading to the endoplasmic reticulum (ER) stress. The obtained results demonstrated that C/EBP β directly induces the upregulation of miR-1a-3p by binding to its promoter. Furthermore, as a direct allosteric AMPK activator, metformin was shown to activate AMPK, and significantly reduces C/EBP β and miR-1a-3p level, compared with those in the control group. In conclusion, metformin protects cardiomyocytes against H 2 O 2 damage through AMPK/ C/EBP β/miR-1a-3p/GRP94 pathway, which indicates that metformin may be applied for the treatment of I/R injury.