MiR-125b downregulates macrophage scavenger receptor type B1 and reverse cholesterol transport

Miguel Hueso,Raquel Griñán,Adrián Mallen,Estanislao Navarro,Elvira Purqueras,Montse Gomá,Fabrizio Sbraga,Arnau Blasco-Lucas,Giovanna Revilla,David Santos,Marina Canyelles,Josep Julve,Joan Carles Escolà-Gil,Noemi Rotllan

doi:10.1016/j.biopha.2021.112596

Abstract

ObjectiveTo determine whether miR-125b regulates cholesterol efflux in vivo and in vitro through the regulation of scavenger receptor type B1 (SR-B1). Approach and resultsWe demonstrated that miR-125b is up-regulated in the human aortas of patients with CAD and is located in macrophages and vascular smooth muscle cells (VSMCs). We identified SCARB1 as a direct target of miR-125b by repressing the activity of the SCARB1 3′-untranslated region reporter construct. Moreover, the overexpression of miR-125b in both human and mouse macrophages as well as VSMCs was found to downregulated the expression of the SCARB1 and the SR-B1 protein levels, thereby impairing α-HDL-mediated macrophage cholesterol efflux in vitro. The in vivo reverse cholesterol transport (RCT) rate from non-cholesterol-loaded macrophages transfected with miR-125b to feces was also found to be decreased when compared with that of control mimic-transfected macrophages. ConclusionsTogether, these results provide evidence that miR-125b downregulates SCARB1 and SR-B1 in both human and mouse macrophages as well as VSMCs, thereby impairing macrophage cholesterol efflux in vitro and the whole macrophage-specific RCT pathway in vivo.

Highlights

The accumulation of macrophages in the artery wall, and the sub sequent foam cells formation are hallmarks of vascular lesions in atherosclerosis (ATH) progression
Since scavenger receptor type B1 (SR-B1) is highly expressed in foam cells within human aortic ATH [13], here, we aimed to evaluate the role of miR-125b in regulating SR-B1-mediated macrophage as well as vascular smooth muscle cells (VSMCs) cholesterol efflux to high-density lipo proteins (HDL) particles in vitro and the entire macrophage-specific reverse cholesterol transport (RCT) pathway in vivo
MiR-125b has been reported to be highly expressed in vascular murine ECs [20], and it was physiologically expressed in murine steroidogenic cells, at much lower levels than miR-125a, which targeted the SCARB1 gene and downregulated the SR-B1-mediated se lective HDL cholesterol esters uptake [12]

Summary

Introduction

The accumulation of macrophages in the artery wall, and the sub sequent foam cells formation are hallmarks of vascular lesions in atherosclerosis (ATH) progression. Since macrophages do not express pathways for catabolizing cholesterol, the ability of high-density lipo proteins (HDL) particles to stimulate the efflux of excess free cholesterol is critical in reducing foam cell formation [1]. SR-B1 is widely expressed throughout the different cell types and both preclinical experimental and clinical studies have shown that the disruption of SR-B1 function predisposes to the development of ATH and cardiovas cular disease [3,4], there is a controversy in different human. Other cell types, such endothelial (ECs) and vascular smooth muscle cells (VSMCs) can become foam cells [8,9], the contribution of SR-BI-mediated cholesterol efflux pathways on foam cell formation in these particular cell types remains unknown

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