Mitochondrial Fission Is Required for Angiotensin II-Induced Cardiomyocyte Apoptosis Mediated by a Sirt1-p53 Signaling Pathway.

Jia Qi,Yanggang Yuan,Ping Yang,Jihui Chen,Junli Duan,Feng Wang,Xuelian Wang,Renjie Xu,Zhaoyang Lu

doi:10.3389/fphar.2018.00176

Jia Qi, Yanggang Yuan + Show 7 more

Open Access

https://doi.org/10.3389/fphar.2018.00176

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Abstract

Hypertension-induced cardiac apoptosis is a major contributor to early-stage heart-failure. Our previous studies have found that p53-mediated mitochondrial fission is involved in aldosterone-induced podocyte apoptosis. However, it is not clear that whether p53-induced mitochondrial fission is critical for hypertensive Angiotensin II (AngII)-induced cardiomyocyte apoptosis. In this study, we found that inhibition of the mitochondrial fission protein Drp1 (dynamin-related protein 1) by Mdivi-1 prevented cardiomyocyte apoptosis and cardiac remodeling in SHRs. In vitro we found that treatment of cultured neonatal rat cardiomyocytes with AngII induced Drp1 expression, mitochondrial fission, and apoptosis. Knockdown of Drp1 inhibited AngII-induced mitochondrial fission and cardiomyocyte apoptosis. Furthermore, AngII induced p53 acetylation. Knockdown of p53 inhibited AngII-induced Drp1 expression, mitochondrial fission, and cardiomyocyte apoptosis. Besides, we found that Sirt1 was able to reverse AngII-induced p53 acetylation and its binding to the Drp1 promoter, which subsequently inhibited mitochondrial fission and eventually attenuated cardiomyocyte apoptosis. Collectively, these results suggest that AngII degrades Sirt1 to increase p53 acetylation, which induces Drp1 expression and eventually results in cardiomyocyte apoptosis. Sirt1/p53/Drp1dependent mitochondrial fission may be a valuable therapeutic target for hypertension induced heart failure.

Highlights

Cardiomyocyte apoptosis has been demonstrated to occur in a variety of cardiovasculardiseases
Our present work shows that inhibiting mitochondrial fission by Mdivi-1 prevents cardiomyocyte apoptosis and attenuates cardiac remodeling in SHRs
In vitro we found that Angiotensin II (AngII) induced mitochondrial fission and apoptosisvia an elaborate mechanism, involving transcriptionally activation of Drp1 through p53 acetylation induced by Sirt1 degradation

Summary

Introduction

Cardiomyocyte apoptosis has been demonstrated to occur in a variety of cardiovasculardiseases. Many previous studies have reported that Angiotensin II (AngII) is involved in cardiac hypertrophy and apoptosis (Herichova and Szantoova, 2013). Mitochondrial Fission Mediates Hypertensive Cardiomyopathy cardiomyocyte apoptosis (Mehta and Griendling, 2007). Abnormal mitochondrial fission is involved in the regulation of apoptosis (Li et al, 2010). Previous studies have reported that mitochondria often fragment into smaller units during apoptosis. AngII was found to induce apoptosis through Drp dependent mitochondrial fission in human umbilical vein endothelial cells (HUVECs) (Chen et al, 2016). Whether Drp dependent mitochondrial fission participates in the hypertension induced cardiomyocyte apoptosis and the detailed mechanisms underlying Drp gene regulation by AngII are still largely unknown

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