title: SIRT1-mediated epigenetic downregulation of plasminogen activator inhibitor-1 prevents vascular endothelial replicative senescence.
abstract: The inactivation of plasminogen activator inhibitor-1 (PAI-1) has been shown to exert beneficial effects in age-related vascular diseases. Limited information is available on the molecular mechanisms regarding the negatively regulated expression of PAI-1 in the vascular system. In this study, we observed an inverse correlation between SIRT1, a class III histone deacetylase, and PAI-1 expression in human atherosclerotic plaques and the aortas of old mice, suggesting that internal negative regulation exists between SIRT1 and PAI-1. SIRT1 overexpression reversed the increased PAI-1 expression in senescent human umbilical vein endothelial cells (HUVECs) and aortas of old mice, accompanied by decreased SA-β-gal activity in vitro and improved endothelial function and reduced arterial stiffness in vivo. Moreover, the SIRT1-mediated inhibition of PAI-1 expression exerted an antisenescence effect in HUVECs. Furthermore, we demonstrated that SIRT1 is able to bind to the PAI-1 promoter, resulting in a decrease in the acetylation of histone H4 lysine 16 (H4K16) on the PAI-1 promoter region. Thus, our findings suggest that the SIRT1-mediated epigenetic inhibition of PAI-1 expression exerts a protective effect in vascular endothelial senescence.
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Yan-Zhen
authors.initials: YZ
authors.lastname: Wan
authors.forename: Peng
authors.initials: P
authors.lastname: Gao
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhou
authors.forename: Zhu-Qin
authors.initials: ZQ
authors.lastname: Zhang
authors.forename: De-Long
authors.initials: DL
authors.lastname: Hao
authors.forename: Li-Shan
authors.initials: LS
authors.lastname: Lian
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Li
authors.forename: Hou-Zao
authors.initials: HZ
authors.lastname: Chen
authors.forename: De-Pei
authors.initials: DP
authors.lastname: Liu
mesh_terms: D000818:Animals; D016922:Cellular Senescence / Q000502:physiology*; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058226:Plaque, Atherosclerotic / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics* / Q000378:metabolism; D058258:Serpin E2 / Q000235:genetics* / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D058258:Serpin E2; C511869:Serpine2 protein, mouse; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: H4K16 acetylation; PAI-1; SIRT1; atherosclerosis; endothelial replicative senescence; epigenetic