These authors contributed equally to this work
SIRT1-mediated epigenetic downregulation of plasminogen activator inhibitor-1 prevents vascular endothelial replicative senescence
Article first published online: 18 JUL 2014
© 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Volume 13, Issue 5, pages 890–899, October 2014
How to Cite
Wan, Y.-Z., Gao, P., Zhou, S., Zhang, Z.-Q., Hao, D.-L., Lian, L.-S., Li, Y.-J., Chen, H.-Z. and Liu, D.-P. (2014), SIRT1-mediated epigenetic downregulation of plasminogen activator inhibitor-1 prevents vascular endothelial replicative senescence. Aging Cell, 13: 890–899. doi: 10.1111/acel.12247
- Issue published online: 19 SEP 2014
- Article first published online: 18 JUL 2014
- Manuscript Accepted: 15 JUN 2014
- National Basic Research Program. Grant Numbers: 2011CB503902, 2013CB5300700
- National Natural Science Foundation of China. Grant Numbers: 91339201, 31271227, 30121091
- Beijing Nova Program. Grant Number: XX2013064
- National Science and Technology Support Program. Grant Number: 2012BAI39B02
- endothelial replicative senescence;
- H4K16 acetylation;
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.