Metformin attenuates ischemia/reperfusion-induced apoptosis of cardiac cells by downregulation of p53/microRNA-34a via activation SIRT1.

Metformin has been demonstrated to be beneficial for the treatment of an impaired myocardium as a result of ischemia reperfusion (I/R) injury and miR-34a may be involved in this process. The aim of the present study was to determine the mechanisms by which metformin attenuated myocardial I/R injury induced apoptosis. In the in vivo I/R rat model, metformin reduced the area of damaged myocardium and CKMB activity for protection of the myocardium. Metformin also reduced apoptosis, the expression of apoptosis associated proteins and miR-34a, which resulted in corresponding changes of Bcl-2 expression. To further examine the role of miR-34a, H9C2 cells were transfected by miR-34a mimic and inhibitor. Overexpression of miR-34a increased apoptosis in H9C2 cells induced by OGD/R and knockdown of miR-34a reduced apoptosis. Metformin decreased the deacetylation activity of SIRT 1 resulting in reduced Ac-p53 levels, which reduced the levels of pri-miR-34a. To confirm these results clinically, 90 patients with ST-segment elevation myocardial infarction following percutaneous coronary intervention were recruited. Patients who took metformin regularly before infarction had lower miR-34a levels and lower serum CKMB activity. Metformin also improved sum ST-segment recovery following I/R injury. In conclusion, metformin may be helpful in the treatment of myocardial ischemia reperfusion.