Poly (ADP-ribose) polymerase inhibition protects against myocardial ischaemia/reperfusion injury via suppressing mitophagy.

ABSTRACT: Myocardial ischaemia/reperfusion (I/R) injury attenuates the beneficial effects of reperfusion therapy. Poly(ADP-ribose) polymerase (PARP) is overactivated during myocardial I/R injury. Mitophagy plays a critical role in the development of myocardial I/R injury. However, the effect of PARP activation on mitophagy in cardiomyocytes is unknown. In this study, we found that I/R induced PARP activation and mitophagy in mouse hearts. Poly(ADP-ribose) polymerase inhibition reduced the infarct size and suppressed mitophagy after myocardial I/R injury. In vitro, hypoxia/reoxygenation (H/R) activated PARP, promoted mitophagy and induced cell apoptosis in cardiomyocytes. Poly(ADP-ribose) polymerase inhibition suppressed H/R-induced mitophagy and cell apoptosis. Parkin knockdown with lentivirus vectors inhibited mitophagy and prevented cell apoptosis in H/R-treated cells. Poly(ADP-ribose) polymerase inhibition prevented the loss of the mitochondrial membrane potential (??m). Cyclosporin A maintained ??m and suppressed mitophagy but FCCP reduced the effect of PARP inhibition on ??m and promoted mitophagy, indicating the critical role of ??m in H/R-induced mitophagy. Furthermore, reactive oxygen species (ROS) and poly(ADP-ribosylation) of CypD and TSPO might contribute to the regulation of ??m by PARP. Our findings thus suggest that PARP inhibition protects against I/R-induced cell apoptosis by suppressing excessive mitophagy via the ??m/Parkin pathway.

SUBMITTER: Cao S 

PROVIDER: S-EPMC6787458 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature