Department of Cardiovascular Medicine, The First Affiliated Hospital of the Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Int J Mol Med. 2014 Mar;33(3):550-8. doi: 10.3892/ijmm.2014.1619. Epub 2014 Jan 8.
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.
雌激素对心血管疾病有多种作用，但其中的机制尚不完全清楚。胆固醇外排是预防泡沫细胞形成和动脉粥样硬化发展的关键机制。最近的研究强调了血管平滑肌细胞（VSMC）衍生的泡沫细胞在动脉粥样硬化形成中的作用。然而，雌激素是否促进 VSMC 中的胆固醇外流并抑制 VSMC 衍生的泡沫细胞形成仍不清楚。在本研究中，我们表明 17β-雌二醇（E2）显著增强了胆固醇向载脂蛋白（apo）A-1 和高密度脂蛋白（HDL）的外流，并减轻了氧化低密度脂蛋白（ox-LDL）诱导的 VSMC 中胆固醇酯的积累，这与 ATP 结合盒转运蛋白 ABCA1 和 ABCG1 的表达增加有关。E2 通过激活肝 X 受体（LXR）α 上调 ABCA1 和 ABCG1 的表达，这通过用药理学抑制剂或小干扰 RNA（siRNA）抑制 LXRα 后 ABCA1 和 ABCG1 的表达来证实。此外，E2 通过雌激素受体（ER）增加 VSMC 中的 LXRα、ABCA1 和 ABCG1 表达，通过使用选择性 ERα 或 ERβ 拮抗剂（MPP 和 PHTPP）和激动剂（PPT 和 DPN）证实了 ERβ 的参与。这些发现表明，E2 通过 ERβ 和 LXRα 依赖性上调 ABCA1 和 ABCG1 促进 VSMC 中的胆固醇外流并减少 VSMC 衍生的泡沫细胞形成，为雌激素的抗动脉粥样硬化特性提供了新的见解。
