Vascular Smooth Muscle Cell Sirtuin 1 Protects Against DNA Damage and Inhibits Atherosclerosis

Abstract

Background— Vascular smooth muscle cells (VSMCs) in human atherosclerosis manifest extensive DNA damage and activation of the DNA damage response, a pathway that coordinates cell cycle arrest and DNA repair, or can trigger apoptosis or cell senescence. Sirtuin 1 deacetylase (SIRT1) regulates cell ageing and energy metabolism and regulates the DNA damage response through multiple targets. However, the direct role of SIRT1 in atherosclerosis and how SIRT1 in VSMCs might regulate atherosclerosis are unknown. Methods and Results— SIRT1 expression was reduced in human atherosclerotic plaques and VSMCs both derived from plaques and undergoing replicative senescence. SIRT1 inhibition reduced DNA repair and induced apoptosis, in part, through reduced activation of the repair protein Nijmegen Breakage Syndrome-1 but not p53. Fat feeding reduced SIRT1 and induced DNA damage in VSMCs. VSMCs from mice expressing inactive truncated SIRT1 (Δex4) showed increased oxidized low-density lipoprotein–induced DNA damage and senescence. ApoE −/− mice expressing SIRT1 Δex4 only in smooth muscle cells demonstrated increased DNA damage response activation and apoptosis, increased atherosclerosis, reduced relative fibrous cap thickness, and medial degeneration. Conclusions— SIRT1 is reduced in human atherosclerosis and is a critical regulator of the DNA damage response and survival in VSMCs. VSMC SIRT1 protects against DNA damage, medial degeneration, and atherosclerosis.