Anti-vascular ageing effects of endothelial SIRT1 - communicating with smooth muscle cells of the arteries

Abstract

Arterial remodeling is not only a physiological process during the formation of blood vessels, but also plays an important role in the development of cardiovascular diseases. Crosstalks between the endothelium and the surrounding vascular smooth muscle cells control the arterial remodeling process in response to changes in blood flow and nutrient supply. Endothelial disruption and dysfunction facilitate the adverse arterial remodeling and alter the mechanical responses of the blood vessel wall. Despite this information, little is known about the molecular pathways by which arterial remodeling is controlled and regulated. SIRT1 is a longevity regulator possessing potent anti-cardiometabolic ageing properties. The present study identifies endothelial SIRT1 as a key modulator of arterial remodeling. SIRT1 facilitates the ubiquitination and proteasomal degradation of LKB1, a senescence-inducing factor in endothelial cells. LKB1 binds to the promoter sequences of a gene encoding transforming growth factor beta (TGFbeta). By promoting the protein complex formation with HERC2, a giant scaffold protein possessing an E3 ligase activity, SIRT1 mediates the selective degradation of acetylated LKB1, thus preventing the trans-activation of TGFbeta. In mice, overexpression of SIRT1 in endothelial cells abolishes the hypertrophic arterial remodeling caused by eNOS deficiency. In conclusion, SIRT1 prevents endothelial senescence-induced pathological vascular remodeling and represents a promising anti-vascular ageing drug target for the prevention of diseases such as restenosis, hypertension and atherosclerosis.