Sp1 Targeted PARP1 Inhibition Protects Cardiomyocytes From Myocardial Ischemia-Reperfusion Injury via Downregulation of Autophagy.

Yifeng Xu,Yunfei Deng,Boqian Wang,Yanqi Zhu,Feng Zhu,Hongli Li,Xiaoxiao Liu,Yanyan Liang

doi:10.3389/fcell.2021.621906

Abstract

Myocardial ischemia–reperfusion injury (MIRI), characterized by post-ischemic cardiomyocytes death and reperfusion myocardial damage, is a lethal yet unresolved complication in the treatment of acute myocardial infarction (AMI). Previous studies have demonstrated that poly(ADP-ribose) polymerase-1 (PARP1) participates in the progression of various cardiovascular diseases, and various reports have proved that PARP1 can be a therapeutic target in these diseases, but whether it plays a role in MIRI is still unknown. Therefore, in this study, we aimed to explore the role and mechanism of PARP1 in the development of MIRI. Firstly, we demonstrated that PARP1 was activated during MIRI-induced myocardial autophagy in vitro. Moreover, PARP1 inhibition protected cardiomyocytes from MIRI through the inhibition of autophagy. Next, we discovered that specificity protein1 (Sp1), as a transcription factor of PARP1, regulates its target gene PARP1 through binding to its target gene promoter during transcription. Furthermore, silencing Sp1 protected cardiomyocytes from MIRI via the inhibition of PARP1. Finally, the functions and mechanisms of PARP1 in the development of MIRI were also verified in vivo with SD rats model. Based on these findings, we concluded that PARP1 inhibition protects cardiomyocytes from MIRI through the inhibition of autophagy, which is targeted by Sp1 suppression. Therefore, the utilization of PARP1 exhibits great therapeutic potential for MIRI treatment in future.

Highlights

Acute myocardial infarction (AMI), associated with high mortality and morbidity, is one of the major causes of death in the world (Penna et al, 2013; Pu et al, 2014)
Since we have proved that there was a targeted regulation between specificity protein 1 (Sp1) and Poly(ADP-ribose) polymerase-1 (PARP1), we still transfected H9c2 cells with Sp1 shRNA as well as Sp1 shRNA-negative control (NC) for 72 h and treating cardiomyocytes with 10 uM AG-14361 for 1 h to explore the association between Sp1 and PARP1 in the development of Oxygen-Glucose Deprivation/Reperfusion (OGD/R) in H9c2 cells
Myocardial ischemia-reperfusion injury (MIRI) has been reported to be associated with autophagy, and this disease can increase the level of autophagy in cardiomyocytes (Kloner and Jennings, 2001; Rochitte et al, 1998; Baines, 2011; Thapalia et al, 2014)

Summary

Introduction

Acute myocardial infarction (AMI), associated with high mortality and morbidity, is one of the major causes of death in the world (Penna et al, 2013; Pu et al, 2014). Myocardial reperfusion is likely to cause an excessive production of reactive oxygen species (ROS), contributing to the activation of autophagy, the induction of post-ischemic cardiomyocyte death, and the generation of cardiac dysfunction, which was termed as myocardial ischemiareperfusion injury (MIRI) (Movassagh and Foo, 2008; Gustafsson and Gottlieb, 2009; Morales et al, 2014). PARP1 inhibition was proved to be cardiac-protective in heart failure and post-infarction myocardial remodeling (Halmosi et al, 2016), but whether it is involved in MIRI is unknown

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