MicroRNA-15a inhibition protects against hypoxia/reoxygenation-induced apoptosis of cardiomyocytes by targeting mothers against decapentaplegic homolog 7

Myocardial ischemia/reperfusion (I/R) injury is a major pathological process in coronary heart disease and cardiac surgery, and is associated with aberrant microRNA (miR) expression. Previous studies have demonstrated that inhibition of miR-15a expression may ameliorate I/R-induced myocardial injury. In the present study, the potential role and underlying mechanism of miR-15a in hypoxia/reoxygenation-induced apoptosis of cardiomyocytes was investigated. Myocardial I/R was simulated in cultured H9c2 cells by 24 h hypoxia followed by 24 h reoxygenation. Using recombinant lentivirus vectors, the inhibition of miR-15a was indicated to significantly reduce cardiomyocyte apoptosis and release of lactate dehydrogenase and malondialdehyde. Conversely, upregulated miR-15a expression was pro-apoptotic. Mothers against decapentaplegic homolog 7 (SMAD7) was identified by bioinformatics analysis as a potential target of miR-15a. Luciferase reporter assays and western blotting for endogenous SMAD7 protein indicated that miR-15a inhibited SMAD7 expression via its 3′-untranslated region. Nuclear levels of nuclear factor-κB (NF-κB) p65 were increased by miR-15a expression and decreased by miR-15a inhibition, which is consistent with the possibility that the inhibition of SMAD7 by miR-15a results in NF-κB activation. These findings suggested that the therapeutic effects of miR-15a inhibition on I/R injury may potentially be explained by its ability to release SMAD-7-dependent NF-κB inhibition. This may provide evidence for miR-15a as a potential therapeutic target for the treatment of cardiac I/R injury.