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

作者：Yang Zhang, Xiaoman Wang, Xun-Kai Li, Shuangjie Lv, Heping Wang, Yang Liu, Jingyue Zhou, Hui Gong, Xiaofeng Chen, Sichong Ren, Huina Zhang, Yuxiang Dai, Hua Cai, Bo Yan, Hou‐Zao Chen, Xiaoqiang Tang · 发表于：European Heart Journal · 年份：2023 · DOI：10.1093/eurheartj/ehad381 · 被引用次数：78 · 研究领域：Sirtuins and Resveratrol in Medicine、Cardiovascular Health and Disease Prevention、Lipid metabolism and disorders

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 aggravati...