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

• Published in: Molecular therapy. Nucleic acids 2018-12, Vol.13, p.189-197
• Main Authors: Zhang, Ying, Liu, Xue, Zhang, Lu, Li, Xuelian, Zhou, Zhongqiu, Jiao, Lei, Shao, Yingchun, Li, Mengmeng, Leng, Bing, Zhou, Yuhong, Liu, Tianyi, Liu, Qiushuang, Shan, Hongli, Du, Zhimin
• Format: Article
• Language: English
• Subjects: endoplasmic reticulum stress; ischemia-reperfusion injury; microRNA
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2018.09.001

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.