Sirtuin 2 deficiency aggravates ageing-induced vascular remodelling in humans and mice

Yang Zhang; Xiaoman Wang; Xun-Kai Li; Shuang-Jie Lv; He-Ping Wang; Yang Liu; Jingyue Zhou; Hui Gong; Xiao-Feng Chen; Si-Chong Ren; Huina Zhang; Yuxiang Dai; Hua Cai; Bo Yan; Hou-Zao Chen; Xiaoqiang Tang

doi:10.1093/eurheartj/ehad381

Sirtuin 2 deficiency aggravates ageing-induced vascular remodelling in humans and mice

Eur Heart J. 2023 Aug 1;44(29):2746-2759. doi: 10.1093/eurheartj/ehad381.

Authors

Yang Zhang¹, Xiaoman Wang¹, Xun-Kai Li¹, Shuang-Jie Lv¹, He-Ping Wang¹, Yang Liu^{2

3}, Jingyue Zhou^{2

4

5}, Hui Gong^{2

6}, Xiao-Feng Chen⁷, Si-Chong Ren⁸, Huina Zhang⁹, Yuxiang Dai¹⁰, Hua Cai^{11

12}, Bo Yan¹³, Hou-Zao Chen^{1

14}, Xiaoqiang Tang^{2

4

5}

Affiliations

¹ Department of Biochemistry & Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, China.
² Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, No.17 People's South Road, Chengdu, Sichuan 610041, China.
³ Division of Vascular Surgery, Department of General Surgery, and Laboratory of Cardiovascular Diseases, West China Hospital, Sichuan University, No.17 People's South Road, Chengdu, Sichuan 610041, China.
⁴ National Health Commission Key Laboratory of Chronobiology, Sichuan University, No.17 People's South Road, Chengdu, Sichuan 610041, China.
⁵ Development and Related Diseases of Women and Children, Key Laboratory of Sichuan Province, West China Second University Hospital, Sichuan University, No.17 People's South Road, Chengdu, Sichuan 610041, China.
⁶ National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No.17 People's South Road, Chengdu, Sichuan 610041, China.
⁷ School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Chengdu, Sichuan 611137, China.
⁸ Department of Nephrology, First Affiliated Hospital of Chengdu Medical College, 783 Xindu Avenue, Chengdu, Sichuan 610500, China.
⁹ Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, No. 2 Anzhen Road, Beijing 10029, China.
¹⁰ Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, 180 Fenglin Road, Shanghai 200032, China.
¹¹ Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA.
¹² Division of Cardiology, Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA.
¹³ Institute of Precision Medicine, Jining Medical University, 133 Hehua Road, Taibaihu New District, Jining, Shandong 272067, China.
¹⁴ Medical Epigenetics Research Center, Chinese Academy of Medical Sciences, 5 Dong Dan San Tiao, Beijing 100005, China.

Abstract

Aims: The mechanisms underlying ageing-induced vascular remodelling remain unclear. This study investigates the role and underlying mechanisms of the cytoplasmic deacetylase sirtuin 2 (SIRT2) in ageing-induced vascular remodelling.

Methods and results: Transcriptome and quantitative real-time PCR data were used to analyse sirtuin expression. Young and old wild-type and Sirt2 knockout mice were used to explore vascular function and pathological remodelling. RNA-seq, histochemical staining, and biochemical assays were used to evaluate the effects of Sirt2 knockout on the vascular transcriptome and pathological remodelling and explore the underlying biochemical mechanisms. Among the sirtuins, SIRT2 had the highest levels in human and mouse aortas. Sirtuin 2 activity was reduced in aged aortas, and loss of SIRT2 accelerated vascular ageing. In old mice, SIRT2 deficiency aggravated ageing-induced arterial stiffness and constriction-relaxation dysfunction, accompanied by aortic remodelling (thickened vascular medial layers, breakage of elastin fibres, collagen deposition, and inflammation). Transcriptome and biochemical analyses revealed that the ageing-controlling protein p66Shc and metabolism of mitochondrial reactive oxygen species (mROS) contributed to SIRT2 function in vascular ageing. Sirtuin 2 repressed p66Shc activation and mROS production by deacetylating p66Shc at lysine 81. Elimination of reactive oxygen species by MnTBAP repressed the SIRT2 deficiency-mediated aggravation of vascular remodelling and dysfunction in angiotensin II-challenged and aged mice. The SIRT2 coexpression module in aortas was reduced with ageing across species and was a significant predictor of age-related aortic diseases in humans.

Conclusion: The deacetylase SIRT2 is a response to ageing that delays vascular ageing, and the cytoplasm-mitochondria axis (SIRT2-p66Shc-mROS) is important for vascular ageing. Therefore, SIRT2 may serve as a potential therapeutic target for vascular rejuvenation.

Keywords: Ageing; Arterial stiffness; SIRT2; Vascular remodelling; mROS; p66Shc.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aging
Animals
Humans
Mice
Mice, Knockout
Reactive Oxygen Species / metabolism
Sirtuin 2* / metabolism
Src Homology 2 Domain-Containing, Transforming Protein 1
Vascular Remodeling*

Substances

Sirtuin 2
SHC1 protein, human
Src Homology 2 Domain-Containing, Transforming Protein 1
Reactive Oxygen Species