Sirtuin 3 Deficiency Accelerates Hypertensive Cardiac Remodeling by Impairing Angiogenesis

• DOI: 10.1161/jaha.117.006114
• Publication Date: 2017-09-01T18:25:38Z
• Authors: Tong Wei; Gaojian Huang; Jing Gao; Chenglin Huang; Mengwei Sun; Jian Wu; Juan Bu; Weili Shen
• Keywords: Mice, 129 Strain; Neovascularization, Physiologic; Cardiomegaly; Collagen Type I; Mitochondria, Heart; angiogenesis; 03 medical and health sciences; Sirtuin 3; oxidative stress; Diseases of the circulatory (Cardiovascular) system; Animals; Genetic Predisposition to Disease; Cells, Cultured; Original Research; Mice, Knockout; 0303 health sciences; Angiotensin II; Myocardium; Mitophagy; Acetylation; Fibrosis; 3. Good health; mitochondria; Disease Models, Animal; Oxidative Stress; mitophagy; Collagen Type III; Phenotype; RC666-701; Hypertension; Disease Progression; cardiac remodeling

Background

Emerging evidence indicates that impaired angiogenesis may contribute to hypertension‐induced cardiac remodeling. The nicotinamide adenine dinucleotide–dependent deacetylase Sirtuin 3 ( SIRT 3) has the potential to modulate angiogenesis, but this has not been confirmed. As such, the aim of this study was to examine the relationship between SIRT 3‐mediated angiogenesis and cardiac remodeling.

Methods and Results

Our experiments were performed on SIRT 3 knockout and age‐matched wild‐type mice infused with angiotensin II (1400 ng/kg per minute) or saline for 14 days. After angiotensin II infusion, SIRT 3 knockout mice developed more severe microvascular rarefaction and functional hypoxia in cardiac tissues compared with wild‐type mice. These events were concomitant with mitochondrial dysfunction and enhanced collagen I and collagen III expression, leading to cardiac fibrosis. Silencing SIRT 3 facilitated angiotensin II –induced aberrant Pink/Parkin acetylation and impaired mitophagy, while excessive mitochondrial reactive oxygen species generation limited angiogenic capacity in primary mouse cardiac microvascular endothelial cells. Moreover, SIRT 3 overexpression in cardiac microvascular endothelial cells enhanced Pink/Parkin‐mediated mitophagy, attenuated mitochondrial reactive oxygen species generation, and restored vessel sprouting and tube formation. In parallel, endothelial cell–specific SIRT 3 transgenic mice showed decreased fibrosis, as well as improved cardiac function and microvascular network, compared with wild‐type mice with similar stimuli.

Conclusions

Collectively, these findings suggest that SIRT 3 could promote angiogenesis through attenuating mitochondrial dysfunction caused by defective mitophagy.