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.
Objective. To investigate the protective effects of L-malate against myocardial ischemia/reperfusion (I/R) injury in rats. Methods. Male Sprague-Dawley rats were randomly assigned to the following groups: sham (sham), an ischemia/reperfusion (I/R) model group (model), an DMF pretreated group (DMF), and 5 L-malate pretreated groups (15, 60, 120, 240, or 480 mg/kg, gavage) before inducing myocardial ischemia. Plasma LDH, cTn-I, TNF-α, hs-CRP, SOD, and GSH-PX were measured 3 h later I/R. Areas of myocardial infarction were measured; hemodynamic parameters during I/R were recorded. Hearts were harvested and Western blot was used to quantify Nrf2, Keap1, HO-1, and NQO-1 expression in the myocardium. Results. L-malate significantly reduced LDH and cTn-I release, reduced myocardial infarct size, inhibited expression of inflammatory cytokines, and partially preserved heart function, as well as increasing antioxidant activity after myocardial I/R injury. Western blot confirmed that L-malate reduced Kelch-like ECH-associated protein 1 in ischemic myocardial tissue, upregulated expression of Nrf2 and Nrf2 nuclear translocation, and increased expression of heme oxygenase-1 and NAD(P)H:quinone oxidoreductase 1, which are major targets of Nrf2. Conclusions. L-malate may protect against myocardial I/R injury in rats and this may be associated with activation of the Nrf2/Keap1 antioxidant pathway.
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