Ritonavir binds to and downregulates estrogen receptors: Molecular mechanism of promoting early atherosclerosis

• RTV increases the thickness of rat coronary artery wall and foam cell formation.
• RTV downregulates the expression of ERα and ERβ.
• RTV inhibits ERα promoter activity.
• RTV directly binds to ERα and the key amino acid is Leu536.
• RTV inhibits the nuclear translocation of ERα and GPER.

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.

RTV directly binds to ERα and Leu536 in the hydrophobic core of ligand binding domain is essential for the interaction.Figure optionsDownload high-quality image (266 K)Download as PowerPoint slide