Perivascular Adipose-Derived Exosomes Reduce Foam Cell Formation by Regulating Expression of Cholesterol Transporters.

Yan Liu,Yan Sun,Yujie Zhou,Jianwei Zhang,Chengping Hu,Yong Zhu,Jinxing Liu,Yingxin Zhao,Xuze Lin,Meng Chai,Ang Gao,Dai Zhang,Hongya Han

doi:10.3389/fcvm.2021.697510

Abstract

Background: Accumulating evidence demonstrates that perivascular adipose tissue (PVAT) plays an important role in maintaining vascular homeostasis. The formation of macrophage foam cells is a central feature of atherosclerosis. This study aimed to evaluate the effect of PVAT-derived exosomes (EXOs) on the lipid accumulation of macrophages and verify the anti-atherogenic characteristics of PVAT.Methods and Results: We extracted EXOs from the PVAT and subcutaneous adipose tissue (SCAT) of wild-type C57BL/6J mice. After coincubation, the EXOs were taken up by RAW264.7 cells. Oil Red O staining revealed that macrophage foam cell formation and intracellular lipid accumulation were ameliorated by PVAT-EXOs. Flow cytometry showed that PVAT-EXOs significantly reduced macrophage uptake of fluorescence-labelled oxidised low-density lipoprotein (ox-LDL). In addition, high-density lipoprotein-induced cholesterol efflux was promoted by PVAT-EXOs. Western blot analysis showed the downregulation of macrophage scavenger receptor A and the upregulation of ATP-binding cassette transporter A1 and ATP-binding cassette transporter G1, which could be mediated by the overexpression of peroxisome proliferator-activated receptor γ and was independent of liver X receptor α.Conclusion: Our findings suggest that PVAT-EXOs reduce macrophage foam cell formation by regulating the expression of cholesterol transport proteins, which provides a novel mechanism by which PVAT protects the vasculature from atherosclerosis.

Highlights

Atherosclerosis is a fibrofatty lesion of the artery wall that contributes to stroke, coronary artery disease (CAD), and disabling peripheral artery disease and causes high morbidity and mortality worldwide [1, 2]
Excessive oxidised low-density lipoprotein uptake mediated by macrophage scavenger receptor A (SR-A), the class B scavenger receptor CD36 [3], low-density lipoprotein receptor (LDLR) and lectin-like ox-LDL receptor-1 (LOX-1), as well as reduced cholesterol efflux via ATP-binding cassette transporter A1 (ABCA1) or ATP-binding cassette transporter G1 (ABGA1) [4] contributes to lipid accumulation
We found that Perivascular adipose tissue (PVAT)-derived exosomes significantly downregulated the expression of the cholesterol influx transporter SR-A and upregulated the expression of the cholesterol efflux transporters ABCA1 and ABCG1, thereby reducing cholesterol accumulation in macrophages and the formation of foam cells

Summary

Introduction

Atherosclerosis is a fibrofatty lesion of the artery wall that contributes to stroke, coronary artery disease (CAD), and disabling peripheral artery disease and causes high morbidity and mortality worldwide [1, 2]. The formation of macrophage foam cells plays a crucial role in the pathogenesis of atherosclerosis. The lipid homeostasis of macrophages depends on the dynamic balance of Exosomes and Foam Cell Formation cholesterol uptake, efflux and endogenous synthesis. Terada et al [8] showed that the transplantation of thoracic PVAT induces the TGF-β1-mediated anti-inflammatory response, which exerts an anti-atherogenic effect. Based on these studies, it can be concluded that under physiological conditions, PVAT possesses anti-inflammatory characteristics and inhibits the development of atherosclerosis. Accumulating evidence demonstrates that perivascular adipose tissue (PVAT) plays an important role in maintaining vascular homeostasis. This study aimed to evaluate the effect of PVAT-derived exosomes (EXOs) on the lipid accumulation of macrophages and verify the anti-atherogenic characteristics of PVAT

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