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

Kun Huang,Hanjoong Jo,Jing Echesabal-Chen,Alexis Stamatikos

doi:10.3390/metabo11090640

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.

Highlights

Published: 18 September 2021Atherosclerosis leads to more deaths than any other disease both in the UnitedStates and globally because it is the leading cause of myocardial infarctions and ischemic strokes [1,2]
Our results demonstrate that immortalized mouse aortic endothelial cells (iMAEC) are capable of ABCA1dependent cholesterol efflux (Figure 1C), since apolipoprotein A-I (apoAI) exclusively participates in cholesterol efflux through interaction with ATP binding cassette subfamily A member 1 (ABCA1) [38]
We observed a significant increase in ABCA1 protein expression in both groups of iMAEC exposed to either the endogenous or synthetic LXR/retinoid X receptor (RXR) agonists when compared to vehicle-treated control iMAEC

Summary

Introduction

States and globally because it is the leading cause of myocardial infarctions and ischemic strokes [1,2]. Atherosclerosis is mainly caused by cholesterol accumulating in arteries [3]. The most common treatment for atherosclerosis, oral statin drugs, work to decrease cholesterol levels systemically instead of reducing cholesterol from arteries, and statins are only partially effective against atherosclerosis and preventing myocardial infarctions and ischemic strokes [4,5,6,7]. A better therapy for atherosclerosis and for the prevention of future myocardial infarctions and ischemic strokes may be treatments that are able to safely and effective remove cholesterol precisely from arteries. Recent evidence strongly supports arterial endothelial cell cholesterol accumulation to both trigger and exacerbate atherosclerosis [11,12]

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