PMID- 35123060 OWN - NLM STAT- MEDLINE DCOM- 20220405 LR - 20220526 IS - 1879-3649 (Electronic) IS - 1537-1891 (Linking) VI - 143 DP - 2022 Apr TI - Perivascular adipose-derived exosomes reduce macrophage foam cell formation through miR-382-5p and the BMP4-PPARgamma-ABCA1/ABCG1 pathways. PG - 106968 LID - S1537-1891(22)00017-9 [pii] LID - 10.1016/j.vph.2022.106968 [doi] AB - Background Perivascular adipose tissue (PVAT) releases exosomes (EXOs) to regulate vascular homeostasis. PVAT-derived EXOs reduce macrophage foam cell formation, but the underlying molecular mechanism has yet to be fully elucidated. We hypothesize that PVAT release miRNA through EXOs and regulate the expression of cholesterol transporter of macrophages, thereby reducing foam cell formation. Methods and results Through RT-qPCR, we identified that miR-382-5p, which was expressed at lower levels in PVAT-EXOs from coronary atherosclerotic heart disease patients than healthy individuals, was expressed at higher levels in wild-type C57BL/6 J mouse aortic PVAT-EXOs than in subcutaneous adipose tissue-derived EXOs. We explored macrophage lipid accumulation through oil red O staining, assessed cholesterol uptake and efflux, and verified cholesterol transporter expression. We found that transfection with a miR-382-5p inhibitor offset PVAT-EXO-related reductions in macrophage foam cell formation and increases in cholesterol efflux mediated by ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1). In addition, bone morphogenetic protein 4 (BMP4) pretreatment and si-peroxisome proliferator-activated receptor gamma (PPARgamma) transfection showed that BMP4-PPARgamma participated in PVAT-EXO-mediated upregulation of the cholesterol efflux transporters ABCA1 and ABCG1. Conclusions PVAT-EXOs reduce macrophage foam cell formation through miR-382-5p- and BMP4-PPARgamma-mediated upregulation of the cholesterol efflux transporters ABCA1 and ABCG1. This finding suggests a promising strategy for the prevention and treatment of atherosclerosis. CI - Copyright (c) 2022 Elsevier Inc. All rights reserved. FAU - Liu, Yan AU - Liu Y AD - Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing 100029, China. FAU - Sun, Yan AU - Sun Y AD - Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing 100029, China. FAU - Lin, Xuze AU - Lin X AD - Department of Cardiology, Fuwai Hospital, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China. FAU - Zhang, Dai AU - Zhang D AD - Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing 100029, China. FAU - Hu, Chengping AU - Hu C AD - Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing 100029, China. FAU - Liu, Jinxing AU - Liu J AD - Department of Cardiology, Fuwai Hospital, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China. FAU - Zhu, Yong AU - Zhu Y AD - Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing 100029, China. FAU - Gao, Ang AU - Gao A AD - Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing 100029, China. FAU - Han, Hongya AU - Han H AD - Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing 100029, China. FAU - Chai, Meng AU - Chai M AD - Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing 100029, China. FAU - Zhang, Jianwei AU - Zhang J AD - Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing 100029, China. FAU - Zhao, Yingxin AU - Zhao Y AD - Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing 100029, China. Electronic address: zhaoyingxin@ccmu.edu.cn. FAU - Zhou, Yujie AU - Zhou Y AD - Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing 100029, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220202 PL - United States TA - Vascul Pharmacol JT - Vascular pharmacology JID - 101130615 RN - 0 (ABCA1 protein, human) RN - 0 (ABCA1 protein, mouse) RN - 0 (ABCG1 protein, human) RN - 0 (ABCG1 protein, mouse) RN - 0 (ATP Binding Cassette Transporter 1) RN - 0 (ATP Binding Cassette Transporter, Subfamily G, Member 1) RN - 0 (BMP4 protein, human) RN - 0 (Bmp4 protein, mouse) RN - 0 (Bone Morphogenetic Protein 4) RN - 0 (MIRN382 microRNA, human) RN - 0 (MicroRNAs) RN - 0 (PPAR gamma) SB - IM MH - ATP Binding Cassette Transporter 1/genetics/metabolism MH - ATP Binding Cassette Transporter, Subfamily G, Member 1/genetics/metabolism MH - Adipose Tissue/metabolism MH - Animals MH - Bone Morphogenetic Protein 4/genetics/metabolism MH - *Exosomes/genetics/metabolism MH - Foam Cells/metabolism MH - Humans MH - Macrophages/metabolism MH - Mice MH - Mice, Inbred C57BL MH - *MicroRNAs/genetics/metabolism MH - PPAR gamma/genetics/metabolism OTO - NOTNLM OT - Cholesterol transport proteins OT - Exosome OT - Macrophage foam cell formation OT - Perivascular adipose tissue OT - miRNA EDAT- 2022/02/06 06:00 MHDA- 2022/04/06 06:00 CRDT- 2022/02/05 20:12 PHST- 2021/09/21 00:00 [received] PHST- 2022/01/03 00:00 [revised] PHST- 2022/01/31 00:00 [accepted] PHST- 2022/02/06 06:00 [pubmed] PHST- 2022/04/06 06:00 [medline] PHST- 2022/02/05 20:12 [entrez] AID - S1537-1891(22)00017-9 [pii] AID - 10.1016/j.vph.2022.106968 [doi] PST - ppublish SO - Vascul Pharmacol. 2022 Apr;143:106968. doi: 10.1016/j.vph.2022.106968. Epub 2022 Feb 2.