MiR-139-5p protect against myocardial ischemia and reperfusion (I/R) injury by targeting autophagy-related 4D and inhibiting AMPK/mTOR/ULK1 pathway.

This study aimed at investigating the effect and underlying mechanism of miR-139-5p in myocardial ischemia and reperfusion (I/R) injury. A hypoxia/ reoxygenation (H/R) model was established in H9c2 cardiomyocytes. The level of miR-139-5p was detected in H/R-treated cardiomyocytes, and subsequently, the level of miR-139-5p or its target gene autophagy-related 4D (ATG4D) was up- or downregulated. Furthermore, the cell viability, apoptosis, and autophagy, as well as the expression levels of the proteins related to adenosine 5'-monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/uncoordinated 51-like kinase 1 (ULK1) signaling pathway were determined. The MiR-139-5p was downregulated in H/R-treated cardiomyocytes in comparison to the untreated cells (P < 0.05). H/R treatment significantly decreased the cell viability but increased the cell apoptosis ratio, and autophagy-related proteins levels (P < 0.05). The overexpression of MiR-139-5p significantly promoted cell apoptosis and inhibited cell autophagy induced by H/R (P < 0.05); however, the effects of miR-139-5p on cell apoptosis and cell autophagy were inhibited by its target gene ATG4D (P < 0.05). Furthermore, the upregulated miR-139-5p remarkably inhibited the expression of p-AMPK, p-Raptor, and ULK1, but increased that of p-mTOR (P < 0.05) in H/R-treated cardiomyocytes. The MiR-139-5p has the potential of regulating cell apoptosis and cell autophagy by inhibiting AMPK/mTOR/ULK1 signaling pathway and thereby protecting against myocardial I/R injury.