Oestrogen Inhibits Arterial Calcification by Promoting Autophagy

Abstract

Arterial calcification is a major complication of cardiovascular disease. Oestrogen replacement therapy in postmenopausal women is associated with lower levels of coronary artery calcification, but its mechanism of action remains unclear. Here, we show that oestrogen inhibits the osteoblastic differentiation of vascular smooth muscle cells (VSMCs) in vitro and arterial calcification in vivo by promoting autophagy. Through electron microscopy, GFP–LC3 redistribution, and immunofluorescence analyses as well as measurement of the expression of the autophagosome marker light-chain I/II (LC3I/II) and autophagy protein 5 (Atg5), we show that autophagy is increased in VSMCs by oestrogen in vitro and in vivo. The inhibitory effect of oestrogen on arterial calcification was counteracted by 3-methyladenine (3MA) or knockdown of Atg5 and was increased by rapamycin. Furthermore, the inhibitory effect of oestrogen on arterial calcification and the degree of autophagy induced by oestrogen were blocked by a nonselective oestrogen receptor (ER) antagonist (ICI 182780), a selective oestrogen receptor alpha (ERα) antagonist (MPP), and ERα-specific siRNA. Our data indicate that oestrogen inhibits the osteoblastic differentiation of VSMCs by promoting autophagy through the ERα signalling pathway in vitro and arterial calcification in vivo by increasing autophagy. Our findings provide new insights into the mechanism by which oestrogen contributes to vascular calcification in vitro and in vivo.