Abstract 5777: SIRT1 Inhibits VSMC Proliferation and Migration Underlying Neointima Formation Following Vascular Injury

Abstract

Vascular SMC (VSMC) proliferation and migration are crucial events involved in the pathophys-iology of vascular diseases. SIRT1, a class III histone deacetylase (HDAC), has been implicated in controlling angiogenesis. However, the role of SIRT1 during the response of VSMCs to injury remains unknown. To study the role of SIRT1 in the neointima formation, we generated transgenic mice expressing the human SIRT1 from a minimal SM22α promoter. We demonstrated that in a mouse carotid artery ligation model, SMC-specific overexpression of SIRT1 substantially reduced neointima formation. SIRT1 overexpression inhibited VSMC proliferation and migration, and induced cell cycle arrest at the G1/S transition. Accordingly, overexpression of SIRT1 decreased cyclin D1 and MMP-9 expression at both mRNA and protein level, whereas knockdown of SIRT1 by RNAi resulted in the reverse effect on their protein expression. Moreover, decreased cyclin D1 and MMP-9 expression/activity were observed in injured carotid arteries of SMC-SIRT1 Tg mice. In addition, two components of activator protein-1(AP-1), c-Fos and c-Jun, interacting with and being deacetylated by SIRT1, were involved in the downregulation of cyclin D1 and MMP-9 expression. These findings demonstrate the inhibitive effect of SIRT1 on neointima formation after vascular injury and suggest a potential pharmacological target for prevention of vascular diseases.