Xiang Jin, Wang Ying, Su Ke, Liu Min, Hu Peng-Chao, Ma Tian, Li Jia-Xi, Wei Lei, Zheng Zhongliang, Yang Fang
Ministry of Education Laboratory of Combinatorial Biosynthesis and Drug Discovery, School of Pharmaceutical Science, Wuhan University, Wuhan 430071, PR China.
Department of Pathophysiology, School of Medicine, Wuhan University, Wuhan 430071, PR China.
Exp Cell Res. 2014 Oct 1;327(2):318-30. doi: 10.1016/j.yexcr.2014.07.002. Epub 2014 Jul 10.
Estrogenic actions are closely related to cardiovascular disease. Ritonavir (RTV), a human immunodeficiency virus (HIV) protease inhibitor, induces atherosclerosis in an estrogen-related manner. However, how RTV induce pathological phenotypes through estrogen pathway remains unclear. In this study, we found that RTV increases thickness of coronary artery walls of Sprague Dawley rats and plasma free fatty acids (FFA) levels. In addition, RTV could induce foam cell formation, downregulate both estrogen receptor α (ERα) and ERβ expression, upregulate G protein-coupled estrogen receptor (GPER) expression, and all of them could be partially blocked by 17β-estradiol (E2), suggesting RTV acts as an antagonist for E2. Computational modeling shows a similar interaction with ERα between RTV and 2-aryl indoles, which are highly subtype-selective ligands for ERα. We also found that RTV directly bound to ERα and selectively inhibited the nuclear localization of ERα, and residue Leu536 in the hydrophobic core of ligand binding domain (LBD) was essential for the interaction with RTV. In addition, RTV did not change the secondary structure of ERα-LBD like E2, which explained how ERα lost the capacity of nuclear translocation under the treatment of RTV. All of the evidences suggest that ritonavir acts as an antagonist for 17β-estradiol in regulating α subtype estrogen receptor function and early events of atherosclerosis.
雌激素作用与心血管疾病密切相关。利托那韦（RTV）是一种人类免疫缺陷病毒（HIV）蛋白酶抑制剂，以雌激素相关的方式诱导动脉粥样硬化。然而，RTV如何通过雌激素途径诱导病理表型仍不清楚。在本研究中，我们发现RTV增加了Sprague Dawley大鼠冠状动脉壁厚度和血浆游离脂肪酸（FFA）水平。此外，RTV可诱导泡沫细胞形成，下调雌激素受体α（ERα）和ERβ表达，上调G蛋白偶联雌激素受体（GPER）表达，而17β-雌二醇（E2）可部分阻断所有这些作用，提示RTV作为E2的拮抗剂发挥作用。计算模型显示RTV与2-芳基吲哚在与ERα的相互作用上相似，2-芳基吲哚是ERα的高度亚型选择性配体。我们还发现RTV直接与ERα结合并选择性抑制ERα的核定位，配体结合域（LBD）疏水核心中的Leu536残基对于与RTV的相互作用至关重要。此外，RTV不像E2那样改变ERα-LBD的二级结构，这解释了在RTV处理下ERα如何丧失核转位能力。所有这些证据表明，利托那韦在调节α亚型雌激素受体功能和动脉粥样硬化早期事件中作为17β-雌二醇的拮抗剂发挥作用。
