Sirt1-inducible deacetylation of p21 promotes cardiomyocyte proliferation.

Bing Li,Mengsha Li,Xiang He,Wangjun Liao,Jianping Bin,Hao Zheng,Yanxian Lai,Yulin Liao,Xiaoyun Si,Senlin Huang,Xinzhong Li,Hairui Li

doi:10.18632/aging.102587

Abstract

Inducing cardiomyocyte proliferation is a hopeful approach for cardiac regeneration following myocardial infarction. Previous studies have shown that p21 inhibits the cardiomyocyte proliferation and cardiac regeneration. Deacetylation of p21 by Sirt1 deacetylase may reduce p21 abundance and remove p21-induced cell cycle arrest. However, whether p21 deacetylation and Sirt1 deacetylate control cardiomyocyte proliferation is unclear. Here, we show that acetylation of p21 induces cardiomyocyte proliferation arrest, whereas blocking the acetylation of p21 increases cardiomyocyte proliferation. P21 can be acetylated by Sirt1, and Sirt1 activate p21 ubiquitination through deacetylation. Additionally, overexpression of Sirt1 induces EdU-, pH3-, and Aurora B-positive cardiomyocytes in neonatal and adult mice. In contrast, depletion of Sirt1 reduces cardiomyocyte proliferation in vitro and in vivo. Moreover, Sirt1 protects cardiac function, reduces cardiac remodeling, inhibits cardiomyocyte apoptosis, and attenuates cardiomyocyte hypertrophy post-myocardial infarction. These results suggest that Sirt1-induced p21 deacetylation plays an essential role in cardiomyocyte proliferation and that it could be a novel therapeutic strategy for myocardial infarction.

Highlights

Acute myocardial infarction (MI) causes the rapid death of cardiomyocytes (CMs) with subsequent cardiac dysfunction
We reported that Sirt1-induced p21 deacetylation acts as a novel role promoting CM proliferation
These findings indicate that p21 deacetylation by Sirt1 may be a novel, effective strategy for inducing endogenous cardiac regeneration and protecting the heart from ischemic heart disease

Summary

Introduction

Acute myocardial infarction (MI) causes the rapid death of cardiomyocytes (CMs) with subsequent cardiac dysfunction. Recent studies have demonstrated that the induction of CM proliferation could be a promising way for inducing cardiac regeneration [4, 5]. Previous studies have revealed that p21 inhibits various types of cancer cell cycles [9] and skeletal muscle [10], and bone regeneration [11]. P21 exhibits a regenerationinhibiting role in mammalian heart [12, 13] These reports indicate that p21 plays a powerful inhibitory role in tissue proliferation and regeneration. A previous study showed that p21 can be acetylated by Tip in HCT116 cells [14]. Acetylation makes p21 more stable and unable to be degraded by ubiquitination followed by HCT116 cell cycle arrest [14]. When acetylation proteins become deacetylated, proteins could be depleted by ubiquitination [15]

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