17β-estradiol promotes cholesterol efflux from vascular smooth muscle cells through a liver X receptor α-dependent pathway

Estrogen has pleiotropic effects on the cardiovascular diseases, yet the underlying mechanisms remain incompletely understood. Cholesterol efflux is a key mechanism through which to prevent foam cell formation and the development of atherosclerosis. Recent studies highlight the role of vascular smooth muscle cell (VSMC)-derived foam cells in atherogenesis. However, it remains unclear whether estrogen promotes cholesterol efflux from VSMCs and inhibits VSMC-derived foam cell formation. In the present study, we demonstrated that 17 beta-estradiol (E2) markedly enhanced cholesterol efflux to apolipoprotein (apo)A-1 and high-density lipoprotein (HDL) and attenuated oxidized low-density lipoprotein (ox-LDL) induced cholesteryl ester accumulation in VSMCs, which was associated with an increase in the expression of ATP-binding cassette transporters ABCA1 and ABCG1. The upregulation of ABCA1 and ABCG1 expression by E2 resulted from liver X receptor (LXR)alpha activation, which was confirmed by the prevention of the expression of ABCA1 and ABCG1 after inhibition of LXR alpha with a pharmacological inhibitor or small interfering RNA (siRNA). Furthermore, E2 increased LXR alpha, ABCA1 and ABCG1 expression in VSMCs via the estrogen receptor (ER), and the involvement of ER beta was confirmed by the use of selective ER alpha or ER beta antagonists (MPP and PHTPP) and agonists (PPT and DPN). These findings suggest that E2 promotes cholesterol efflux from VSMCs and reduces VSMC-derived foam cell formation via ER beta- and LXR alpha-dependent upregulation of ABCA1 and ABCG1 and provide novel insights into the anti-atherogenic properties of estrogen.