title: Ritonavir binds to and downregulates estrogen receptors: molecular mechanism of promoting early atherosclerosis.
abstract: 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.
authors.affiliation: Ministry of Education Laboratory of Combinatorial Biosynthesis and Drug Discovery, School of Pharmaceutical Science, Wuhan University, Wuhan 430071, PR China.
authors.forename: Jin
authors.initials: J
authors.lastname: Xiang
authors.affiliation: Department of Pathophysiology, School of Medicine, Wuhan University, Wuhan 430071, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China.
authors.forename: Ke
authors.initials: K
authors.lastname: Su
authors.affiliation: Ministry of Education Laboratory of Combinatorial Biosynthesis and Drug Discovery, School of Pharmaceutical Science, Wuhan University, Wuhan 430071, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Pathophysiology, School of Medicine, Wuhan University, Wuhan 430071, PR China.
authors.forename: Peng-Chao
authors.initials: PC
authors.lastname: Hu
authors.affiliation: Ministry of Education Laboratory of Combinatorial Biosynthesis and Drug Discovery, School of Pharmaceutical Science, Wuhan University, Wuhan 430071, PR China.
authors.forename: Tian
authors.initials: T
authors.lastname: Ma
authors.affiliation: Ministry of Education Laboratory of Combinatorial Biosynthesis and Drug Discovery, School of Pharmaceutical Science, Wuhan University, Wuhan 430071, PR China.
authors.forename: Jia-Xi
authors.initials: JX
authors.lastname: Li
authors.affiliation: Department of Pathophysiology, School of Medicine, Wuhan University, Wuhan 430071, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, PR China. Electronic address: biochem@whu.edu.cn.
authors.forename: Zhongliang
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Department of Physiology, School of Medicine, Wuhan University, Wuhan 430071, PR China. Electronic address: fang-yang@whu.edu.cn.
authors.forename: Fang
authors.initials: F
authors.lastname: Yang
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D002942:Circular Dichroism; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D015536:Down-Regulation; D004967:Estrogens; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005455:Fluorescent Antibody Technique; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics; D011487:Protein Conformation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D011960:Receptors, Estrogen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019438:Ritonavir / Q000494:pharmacology*
chemical_list: D004967:Estrogens; D005230:Fatty Acids, Nonesterified; D017320:HIV Protease Inhibitors; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D019438:Ritonavir
keywords: Estrogen receptor; Estrogenic actions; Macrophage; Ritonavir