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 H₂O₂ in 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.

缺血再灌注（I / R）损伤是缺血性心脏再灌注治疗的主要副作用。很少有疗法可有效地预防由氧化应激诱导的心肌细胞凋亡引起的这种损伤。已显示二甲双胍具有潜在的心脏保护作用和减少心脏事件的能力，但确切机制尚不清楚。在这里，我们旨在确认和调查潜在的二甲双胍活性抗氧化应激对I / R损伤的潜在机制。我们确定在体外暴露于H ₂ O _2的 新生大鼠心室细胞（NRVC）中，miR-1a-3p的表达显着增加。在遭受I / R损伤的小鼠心脏中。显示MiR-1a-3p靶向GRP94的3'UTR，这导致未折叠或错误折叠的蛋白质积累，从而导致内质网（ER）应激。获得的结果证明，C / EBPβ通过与其启动子结合而直接诱导miR-1a-3p的上调。此外，与对照组相比，二甲双胍作为一种直接变构AMPK激活剂，可激活AMPK并显着降低C / EBPβ和miR-1a-3p水平。总之，二甲双胍可通过AMPK / C / EBPβ/ miR-1a-3p / GRP94途径保护心肌细胞免受H ₂ O ₂损害，这表明二甲双胍可用于治疗I / R损伤。