PARP1 promote autophagy in cardiomyocytes via modulating FoxO3a transcription

Cheng Wang,Wenjing Xu,Kai Huang,Yanqing Zhang,Fengxiao Zhang

doi:10.1038/s41419-018-1108-6

Cheng Wang, Wenjing Xu + Show 3 more

Open Access

https://doi.org/10.1038/s41419-018-1108-6

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Abstract

Autophagy is a key regulatory process in maintaining cellular homoeostasis via lysosome degradation. Growing evidence reveals that poly(ADP-ribose) polymerase-1 (PARP1) is involved in the progression of many cardiovascular diseases. This study was undertaken to discuss the role of PARP1 in cardiomyocyte autophagy. Our results demonstrated that PARP1 was activated in response to starvation-induced myocardial autophagy. We identified Forkhead box O (FoxO)3a as a substrate of PARP1. Upon PARP1 activation, poly(ADP-ribosyl)ation dissociated histone H1 from FoxO3a target gene promoter and promoted FoxO3a nuclear accumulation and binding activity to the target promoters, resulting in increased expression of autophagy related genes. Activated autophagy by PARP1 impaired mitochondrial metabolism and promoted cardiomyocyte death. And PARP1 silencing or specific inhibitors alleviated the promotion of FoxO3 activity upon starvation or myocardial ischemia, thus suppressing cardiac apoptosis and fibrosis. Together, these data indicate that PARP1-mediated poly(ADP-ribosyl)ation of FoxO3a plays a key role in cardiomyocyte autophagy. The utilization of PARP1 as a therapeutic target for related cardiovascular diseases would be desirable.

Highlights

Autophagy is an evolutionally conserved mechanism for the turnover of cellular components and organelles via lysosomal degradation[1,2]
Our results proved that poly(ADP-ribose) polymerase-1 (PARP1) could directly bind to and poly(ADPribosyl)ate FoxO3a in cardiomyocytes, which was consistent with a latter research (Fig. S5)
The shhistone H1 treatment dramatically restrained the protection on cell viability from PARP1 inhibition PJ34 or PARP1 knockdown (Fig. 5e–h) all these results suggest that, PARP1 may participate in excessive autophagy induced cell death through histone H1-FoxO3aautophagy pathway

Summary

Introduction

Autophagy is an evolutionally conserved mechanism for the turnover of cellular components and organelles via lysosomal degradation[1,2]. In response to stress, activated autophagy is responsible for the degradation of various macromolecules and organelles including mitochondria, which promotes heart cell survival[2,3]. Forkhead box O (FoxO) subfamily of transcription factors is characterized by a highly conserved Forkhead domain and comprise four members: FoxO1, FoxO3 (FoxO3a), FoxO4 and FoxO64. FoxOs regulate various pathophysiological processes, including cellular atrophy, cell cycle, cell proliferation, and metabolism[4,5,6]. It is well documented that FoxO3a is a positive modifier of autophagy[7]. The transcriptional activity of FoxO3a is conditioned by post-translational modifications such as phosphorylation, acetylation, ubiquitination, and methylation[8,9,10]

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