Treatment with metformin prevents myocardial ischemia-reperfusion injury via STEAP4 signaling pathway.

Abstract

Objective:The aim of the present study was to investigate the underlying mechanism of metformin in reducing myocardial apoptosis and improving mitochondrial function in rats and H9c2 cells subjected to myocardial ischemia–reperfusion (I/R) or hypoxia–reoxygenation (H/R) injuries, respectively.Methods:Following pretreatment with metformin, male Sprague–Dawley rats were used to establish an I/R model in vivo. Serum creatinine kinase-MB and cardiac troponin T levels were examined by enzyme-linked immunosorbent assay. Infarct size and apoptosis were measured by triphenyl tetrazolium chloride staining and terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Pathological changes were evaluated by hematoxylin and eosin staining. H9c2 cells were used to establish an H/R model in vitro. Cell apoptosis and mitochondrial membrane potential (MMP) were examined by flow cytometry and Rhodamine 123. The expression levels of six-transmembrane epithelial antigen of prostate 4 (STEAP4), B-cell lymphoma 2, Bcl-2-associated X protein, and glyceraldehyde 3-phosphate dehydrogenase in both myocardial tissues and H9c2 cells were determined by western blotting.Results:We found that metformin decreased infarct size, increased STEAP4 expression, mitigated myocardial apoptosis, and increased MMP when the models were subjected to H/R or I/R injuries. However, STEAP4 knockdown significantly abrogated the beneficial effect of metformin.Conclusion:We further demonstrated the protective effect of metformin on cardiomyocytes, which might be at least partly attributable to the upregulation of STEAP4. Therefore, STEAP4 might be a new target to decrease apoptosis and rescue mitochondrial function in myocardial I/R injury.