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 cardiomyocyte 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 H2O2in vitro and in the hearts of mice that underwent the I/R injury. MiR-1a-3p was shown to target the 3′ UTR of GRP94, which results in the accumulation of un- or 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 reduce C/EBP β and miR-1a-3p levels compared with those in the control group. In conclusion, metformin protects cardiomyocytes against H2O2 damage through the AMPK/C/EBP β/miR-1a-3p/GRP94 pathway, which indicates that metformin may be applied for the treatment of I/R injury.
Highlights
Myocardial infarction (MI) remains a leading cause of mortality and morbidity worldwide.[1,2] thrombolysis and direct coronary intervention have saved millions of lives, myocardial injury followed by the restoration of blood flow remains a complication of arterial recanalization therapy,[3] and only a few effective therapies are available for prevention of myocardial ischemia-reperfusion (I/R) injury
Metformin Attenuates H2O2-Induced Cardiomyocyte Injury through the Inhibition of miR-1a-3p Expression and Promotion of GRP94 Expression To determine whether metformin could protect primary cardiomyocytes against H2O2-induced cell injury in vitro, we incubated the cardiomyocytes with metformin (0.1, 0.5, 1, 2, 5, or 10 mM) for 30 min before the addition of H2O2 and determined cell viability with the MTT assay
The viability of cardiomyocytes was shown to decrease following the treatment with 100 mM H2O2 for 48 hr, and it increased when the cardiomyocytes were pretreated with 0.5 mM or 1 mM metformin, compared with that in the samples treated with H2O2 only (Figure 1A)
Summary
Myocardial infarction (MI) remains a leading cause of mortality and morbidity worldwide.[1,2] thrombolysis and direct coronary intervention have saved millions of lives, myocardial injury followed by the restoration of blood flow remains a complication of arterial recanalization therapy,[3] and only a few effective therapies are available for prevention of myocardial ischemia-reperfusion (I/R) injury. The identification of more effective treatments for cardiac. Several mechanisms underlying cardiac I/R injury have been proposed: oxidative stress,[4] cellular calcium overload,[5] and inflammatory response.[6]. Molecular Therapy: Nucleic Acids Vol 13 December 2018 a 2018 The Authors.
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