Sirtuin 3 Deficiency Accelerates Hypertensive Cardiac Remodeling by Impairing Angiogenesis.
Tong Wei, Gaojian Huang, Jing Gao, Chenglin Huang, Mengwei Sun, Jian Wu, Juan Bu, Weili Shen
Author Information
Tong Wei: State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China wlshen@sibs.ac.cn.
Gaojian Huang: State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Jing Gao: State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Chenglin Huang: State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Mengwei Sun: Key Laboratory of State General Administration of Sport, Shanghai Research Institute of Sports Science, Shanghai, China.
Jian Wu: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Juan Bu: Department of Macromolecular Science, State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, China.
Weili Shen: State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
BACKGROUND: Emerging evidence indicates that impaired angiogenesis may contribute to hypertension-induced cardiac remodeling. The nicotinamide adenine dinucleotide-dependent deacetylase Sirtuin 3 (SIRT3) 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 SIRT3-mediated angiogenesis and cardiac remodeling. METHODS AND RESULTS: Our experiments were performed on SIRT3 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, SIRT3 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 SIRT3 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, SIRT3 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 SIRT3 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 SIRT3 could promote angiogenesis through attenuating mitochondrial dysfunction caused by defective mitophagy.
