Open AccessSIRT 1‐mediated epigenetic downregulation of plasminogen activator inhibitor‐1 prevents vascular endothelial replicative senescence
Author(s) -
Wan YanZhen,
Gao Peng,
Zhou Shuang,
Zhang ZhuQin,
Hao DeLong,
Lian LiShan,
Li YongJun,
Chen HouZao,
Liu DePei
Publication year - 2014
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12247
Subject(s) - sirtuin 1 , plasminogen activator inhibitor 1 , biology , umbilical vein , downregulation and upregulation , resveratrol , plasminogen activator , acetylation , senescence , epigenetics , histone deacetylase , microbiology and biotechnology , histone , activator (genetics) , tissue plasminogen activator , in vitro , endocrinology , pharmacology , biochemistry , gene
Summary 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 SIRT 1, 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 SIRT 1 and PAI ‐1. SIRT 1 overexpression reversed the increased PAI ‐1 expression in senescent human umbilical vein endothelial cells ( HUVEC s) 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 SIRT 1‐mediated inhibition of PAI ‐1 expression exerted an antisenescence effect in HUVEC s. Furthermore, we demonstrated that SIRT 1 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 SIRT 1‐mediated epigenetic inhibition of PAI ‐1 expression exerts a protective effect in vascular endothelial senescence.