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.

BCL2‑regulated apoptotic process in myocardial ischemia‑reperfusion injury (Review)

“…Although pharmacotherapy is not commonly included in cardioprotective strategies, several investigations have shown that a number of medicines are capable of cushioning the effects of MI/RI ( 176 , 177 , 179 - 182 , 186 - 190 ). The present review briefly reviews those that promote cell survival and reduce apoptosis by affecting the BCL2/Bax ratio through specific signaling pathways.…”

“…Metformin, which is widely used for the treatment of carbohydrate metabolism disorders, inhibits apoptosis in culture (H9c2 cells) and rat cardiomyocytes following injury caused by hypoxia-reoxygenation or ischemia-reoxygenation by increasing the BCL2/BAX ratio with the involvement of metalloreductase STEAP4 ( 177 ). These results in vitro and in vivo affirmed the hypothetical effects of metformin on MI/RI produced by cellular apoptosis inhibition.…”

“…It is important to note that the mechanisms of metabolic cardioprotection of most preparations have been poorly investigated to date (177,(180)(181)(182)(183)(184). The data of different randomized controlled trials often do not prove the effectiveness of the suggested methods (180)(181)(182)(183)(184).…”

Stamp2 Protects From Maladaptive Structural Remodeling and Systolic Dysfunction in Post-Ischemic Hearts by Attenuating Neutrophil Activation

“…Such an effect has been recently reported for the AMP-activated protein kinase (AMPK) activator cilostazol in nonalcoholic fatty liver disease (42). Moreover, in a setting of acute myocardial injury for 2 hours, treatment with the biguanide metformin reduced cardiomyocyte apoptosis in a Stamp2-dependent manner (43). The development of more specific compounds for pharmacological Stamp2 regulation in cardiovascular diseases is therefore an interesting goal for future studies.…”

Effects of Metformin on Ischemia/Reperfusion Injury: New Evidence and Mechanisms

“…Some cardioprotective effects of metformin are mediated for AMPK. This kinase plays an important role in regulating myocardial energy metabolism, and reducing of I/R injury [ 62 , 63 , 64 ]. A recent experimental in vitro study performed by Zhang et al showed that AMPK activation with metformin protected against apoptosis induced by cardiac I/R injury.…”