MiR-302a-3p aggravates myocardial ischemia-reperfusion injury by suppressing mitophagy via targeting FOXO3

This study aimed to investigate whether the protection of miR-302a-3p in myocardial ischemia-reperfusion injury (MIRI) is mediated through the suppression of mitophagy. We constructed a mouse I/R model in vivo by the ligation of left anterior descending coronary artery for 45 min followed by 2 h reperfusion, and an in vitro model by treating mouse cardiomyocytes with hypoxia-reoxygenation (H/R). Knockdown experiments were then performed in vivo and in vitro to determine the effects of miR-302a-3p knockdown on the mitophagy, mitochondrial dysfunction and oxidative stress and apoptosis. The potential targets of miR-302a-3p were further studied by bioinformatics analysis, luciferase assays, quantitative real-time PCR and western blotting. MiR-302a-3p expression was significantly upregulated in mice subjected to MIRI and in H/R-treated mouse cardiomyocytes. Functional analyses demonstrated that inhibition of miR-302a-3p protected cardiac tissues against I/R-induced apoptosis and mitophagy, mitochondrial damage and mitochondrial oxidative stress. Furthermore, FOXO3 was identified as the direct target of miR-302a-3p. Mechanistically, knockdown of FOXO3 partially reversed the cardioprotective effects of miR-302a-3p inhibitor. Our study suggested that inhibition of miR-302a-3p promoted mitochondrial autophagy and inhibited oxidative stress by targeting FOXO3 to suppress myocardial apoptosis, representing a potential target for MIRI treatment.