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

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.

Dynamin‐related protein 1‐mediated mitochondrial fission contributes to IR‐783‐induced apoptosis in human breast cancer cells

“…Increasing evidence indicates that mitochondrial fission promotes the initiation of mitochondrial apoptosis . Our transmission electron microscopy assay revealed that mitochondria presented as elongated filamentous structures in control cells, but exhibited small and punctate mitochondria in IR‐783‐treated cells (Figure A).…”

Renalase Attenuates Mouse Fatty Liver Ischemia/Reperfusion Injury through Mitigating Oxidative Stress and Mitochondrial Damage via Activating SIRT1

“…Previous studies have demonstrated that SIRT1 deacetylates its downstream targets, including NF-κB, Foxos, p53, and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), to regulate apoptosis, inflammation, and oxidative stress and protect organs from IR injury [65]. Additionally, recent studies have shown that the SIRT1/PGC-1α [66] and SIRT1/p53 [67] pathways inhibited Drp1-mediated mitochondrial fission and subsequently induced mitochondrial dysfunction and mitochondriaderived ROS production, resulting in the attenuation of cell apoptosis and death. Consistent with previous studies, our results showed that RNLS administration significantly increased the activity of SIRT1 and protected against oxidative stress injury induced by t-BHP.…”

Mitochondrial function in the heart: the insight into mechanisms and therapeutic potentials

“…Alterations in mitochondrial morphology also contribute to apoptotic responses in the heart. For example, angiotensin II‐induced hypertensive hearts demonstrate a downregulation of SIRT1, thus allowing p53 acetylation and Drp1‐dependent mitochondrial fission, from which mitochondrial fragmentation eventually results in cardiomyocyte apoptosis (Qi et al ., ). Additionally, a down‐regulation of cardiac dual‐specificity protein phosphatase 1 in acute I/R injury activates mitochondrial fission and cardiomyocyte apoptosis (Jin et al ., ).…”