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

Shengchuan Cao,Shujian Wei,Yuguo Chen,Wenjun Wang,Yiying Sun,Qiuhuan Yuan,Bailu Wang,Feng Xu,Qun Zhang,Chang Pan

doi:10.1111/jcmm.14573

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 (ΔΨm). Cyclosporin A maintained ΔΨm and suppressed mitophagy but FCCP reduced the effect of PARP inhibition on ΔΨm and promoted mitophagy, indicating the critical role of ΔΨm in H/R‐induced mitophagy. Furthermore, reactive oxygen species (ROS) and poly(ADP‐ribosylation) of CypD and TSPO might contribute to the regulation of ΔΨm by PARP. Our findings thus suggest that PARP inhibition protects against I/R‐induced cell apoptosis by suppressing excessive mitophagy via the ΔΨm/Parkin pathway.

Highlights

Reperfusion therapy is the most effective treatment for acute myo‐ cardial infarction, reduces ischaemic injury and limits the infarct size
We found that poly(ADP‐ribose) polymerase (PARP) inhibition prevents I/R injury–induced mitophagy and cell apoptosis in cardiomyocytes
Overactivation of PARP depletes intracellular nicotinamide adenine dinucleotide (NAD) and ATP which results in a cellular energy crisis and irreversible cytotoxicity, lead‐ ing to cell necrosis.[6]

Summary

| INTRODUCTION

Reperfusion therapy is the most effective treatment for acute myo‐ cardial infarction, reduces ischaemic injury and limits the infarct size. Several critical factors mediate the detrimental effects of I/R‐induced injury, including oxidative stress, intracellular Ca2+ overload, inflamma‐ tion and mitochondrial permeability transition pore (MPTP) opening.[1,2] The opening of the MPTP is related to poly(ADP‐ribose) polymerase (PARP) activation, and PARP inhibition prevents myocardial I/R injury.[3,4] PARP is a highly conserved DNA‐binding nuclear enzyme family that can be activated by DNA damage. To maintain a healthy and functional mi‐ tochondrial network, dysfunctional or damaged mitochondria are eliminated via a process known as mitochondrial autophagy or mito‐ phagy, which is triggered by starvation, hypoxia and reactive oxygen species (ROS).[7,8] Mitophagy has been classified into canonical and non‐canonical pathways in the heart.[8] The Parkin‐dependent path‐ way is the main form of canonical mitophagy.[9]. This study showed that PARP inhibition attenuated I/R‐ or hypoxia/oxygenation (H/R)‐induced mitophagy and cell apoptosis in vivo and in vitro

| MATERIALS AND METHODS

| DISCUSSION

Findings

CONFLICT OF INTEREST