SIRT 1‐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.

Epigenetics in the Vascular Endothelium

“…This observation suggests that the H4K16 deacetylase activity of SIRT1 may possibly activate these genes by reducing spurious transcript production. Additionally, the loss of SIRT1 in atherosclerotic plaque may de-repress pro-atherosclerotic genes in a H4K16 acetylation dependent manner as suggested for plasminogen activator inhibitor-1 29 . These latter concepts are important in that they highlight a key point.…”

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

“…Another marker of endothelial senescence, PAI-1, is also inhibited by SIRT1 through an epigenetic regulatory mechanism involving the reduction of acetylated histone 4 Lys-16 (H4K16) on the PAI-1 promoter (106,189). Indeed, in senescent ECs and aortas of old mice, improved endothelial function and reduced arterial stiffness have been observed during SIRT1 overexpression that reverses the increased PAI-1 levels (189).…”

Atherosclerosis and the Hydrogen Sulfide Signaling Pathway – Therapeutic Approaches to Disease Prevention

“…It has been reported that mice overexpression of SIRT1 preserved the endothelium function comparing with that of WT littermates fed with high-fat diet and overexpression of SITR1 in ApoE -/- mice developed less atherosclerotic lesions compared with the ApoE -/- controls [61]. The mechanism of SIRT1 improving atherosclerosis may include dilating arteries [59], preserving function of endothelium [60] and preventing endothelial senescence [63], downregulating neointima formation [64] and vascular modeling [65], decreasing Lox-1-induced foam cell formation [62] and protecting against DNA damage [66]. It has been reported that H 2 S upregulated SIRT1 to exert some of its protective effects.…”