Metformin attenuates ischemia/reperfusion-induced apoptosis of cardiac cells by downregulation of p53/microRNA-34a via activation of SIRT1
Abstract
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 model using Sprague-Dawley rats, metformin reduced the area of damaged myocardium and serum creatine MB isoform (CKMB) activity resulting in protection of the myocardium. Metformin also reduced apoptosis and the expression of apoptosis associated proteins, including caspase 3 and cleaved caspase, and decreased the expression of miR-34a, which is upregulated during I/R injury, which in turn resulted in corresponding changes in expression of Bcl-2, a direct target of miR-34a both in vitro and in vivo. To further examine the role of miR-34a in this process, H9C2 cells were transfected by a miR-34a mimic and inhibitor. Overexpression of miR-34a increased apoptosis in H9C2 cells induced by oxygen-glucose deprivation/recovery and knockdown of miR-34a expression-reduced apoptosis under the same conditions. Therefore, the effect of metformin on miR-34a in vitro were assessed. Metformin decreased the deacetylation activity of silent information regulator 1 resulting in reduced Ac-p53 levels, which reduced the levels of pri-miR-34a, and thus in turn reduced miR-34a levels. To confirm these results clinically, 90 patients with ST-segment elevation…
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