title: 17β-estradiol promotes cholesterol efflux from vascular smooth muscle cells through a liver X receptor α-dependent pathway.
abstract: 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 17β-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)α activation, which was confirmed by the prevention of the expression of ABCA1 and ABCG1 after inhibition of LXRα with a pharmacological inhibitor or small interfering RNA (siRNA). Furthermore, E2 increased LXRα, ABCA1 and ABCG1 expression in VSMCs via the estrogen receptor (ER), and the involvement of ERβ was confirmed by the use of selective ERα or ERβ 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 ERβ- and LXRα-dependent upregulation of ABCA1 and ABCG1 and provide novel insights into the anti-atherogenic properties of estrogen.
authors.affiliation: Department of Cardiovascular Medicine, The First Affiliated Hospital of the Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Cardiovascular Medicine, The First Affiliated Hospital of the Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Cardiovascular Medicine, The First Affiliated Hospital of the Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Cardiovascular Medicine, The First Affiliated Hospital of the Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Cardiovascular Medicine, The First Affiliated Hospital of the Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Zhaofei
authors.initials: Z
authors.lastname: Wan
authors.affiliation: Department of Cardiovascular Medicine, The First Affiliated Hospital of the Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Fangyuan
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Cardiovascular Medicine, The First Affiliated Hospital of the Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Cardiovascular Medicine, The First Affiliated Hospital of the Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Cardiovascular Medicine, The First Affiliated Hospital of the Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Zuyi
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism*; D004958:Estradiol / Q000378:metabolism* / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D000071518:Liver X Receptors; D053858:Metabolic Networks and Pathways; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D057093:Orphan Nuclear Receptors / Q000378:metabolism*
chemical_list: D016632:Apolipoprotein A-I; D004967:Estrogens; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; C099252:oxidized low density lipoprotein; D004958:Estradiol; D002784:Cholesterol