Combined LXR and RXR Agonist Therapy Increases ABCA1 Protein Expression and Enhances ApoAI-Mediated Cholesterol Efflux in Cultured Endothelial Cells

• Type of Material: Article
• Authors: Kun Huang, Clemson University; Hanjoong Jo, Emory University; Jing Echesabal-Chen, Clemson University; Alexis Stamatikos, Clemson University
• Language: English
• Date: 2021-09-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2021 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/metabo11090640
• Title of Journal or Parent Work: METABOLITES
• Volume: 11
• Issue: 9
• Grant/Funding Information: This work was supported in part by the USDA National Institute of Food and Agriculture, Hatch project SC-1700577; Accession no. 1021291.; Jing Echesabal-Chen was partially supported by a CU FELLOWS R-Initiatives grant from Clemson University Division of Research.; Cholesterol efflux assays were conducted in Kimberly Paul’s lab, which is supported in part by NIH Eukaryotic Pathogens Innovation Center, Centers of Biomedical Research Excellence grant P20GM109094.
• Keywords: oxysterols; Biochemistry & Molecular Biology; BIOLOGY; INFLAMMATORY RESPONSES; ATHEROSCLEROSIS; CARDIOVASCULAR RISK; cardiovascular disease; Life Sciences & Biomedicine; reverse cholesterol transport; endothelial dysfunction; PHENOTYPE; CELLULAR CHOLESTEROL; A1; DISEASE; endothelial activation; TARGET; atherogenesis; LIVER-X RECEPTORS; vascular inflammation; Science & Technology
• Research Categories: Engineering, Biomedical; Health Sciences, Nutrition

Abstract

Endothelial ABCA1 expression protects against atherosclerosis and this atheroprotective effect is partially attributed to enhancing apoAI-mediated cholesterol efflux. ABCA1 is a target gene for LXR and RXR; therefore, treating endothelial cells with LXR and/or RXR agonists may increase ABCA1 expression. We tested whether treating cultured immortalized mouse aortic endothelial cells (iMAEC) with the endogenous LXR agonist 22(R)-hydroxycholesterol, synthetic LXR agonist GW3965, endogenous RXR agonist 9-cis-retinoic acid, or synthetic RXR agonist SR11237 increases ABCA1 protein expression. We observed a significant increase in ABCA1 protein expression in iMAEC treated with either GW3965 or SR11237 alone, but no significant increase in ABCA1 protein was observed in iMAEC treated with either 22(R)-hydroxycholesterol or 9-cis-retionic acid alone. However, we observed significant increases in both ABCA1 protein expression and apoAI-mediated cholesterol efflux when iMAEC were treated with a combination of either 22(R)-hydroxycholesterol and 9-cis-retinoic acid or GW3965 and SR11237. Furthermore, treating iMAEC with either 22(R)-hydroxycholesterol and 9-cis-retinoic acid or GW3965 and SR11237 did not trigger an inflammatory response, based on VCAM-1, ICAM-1, CCL2, and IL-6 mRNA expression. Based on our findings, delivering LXR and RXR agonists precisely to endothelial cells may be a promising atheroprotective approach.