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Isolation of Adipogenic and Fibro-Inflammatory Stromal Cell Subpopulations from Murine Intra-Abdominal Adipose Depots
Published on: August 16, 2020
Perivascular adipose-derived exosomes reduce macrophage foam cell formation through miR-382-5p and the
1Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing 100029, China.
Abstract:
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 γ (PPARγ) transfection showed that BMP4-PPARγ 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-PPARγ-mediated upregulation of the cholesterol efflux transporters ABCA1 and ABCG1. This finding suggests a promising strategy for the prevention and treatment of atherosclerosis.
Insights
Perivascular adipose tissue exosomes reduce foam cell formation via miR-382-5p and BMP4-PPARγ signaling, upregulating cholesterol transporters ABCA1 and ABCG1. This offers a novel therapeutic strategy for atherosclerosis.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Adipose Tissue Biology
Background:
- Perivascular adipose tissue (PVAT) releases exosomes (EXOs) that modulate vascular homeostasis.
- PVAT-EXOs are known to reduce macrophage foam cell formation, but the precise molecular mechanisms require further elucidation.
- This study investigates the role of microRNAs (miRNAs) within PVAT-EXOs in regulating macrophage cholesterol metabolism.
Purpose of the Study:
- To investigate the role of PVAT-derived exosomes (EXOs) and their miRNA cargo in regulating macrophage cholesterol transport and foam cell formation.
- To identify specific miRNAs involved in PVAT-EXO-mediated effects on cholesterol metabolism.
- To elucidate the signaling pathways, including BMP4-PPARγ, involved in PVAT-EXO-mediated cholesterol efflux.
Main Methods:
- RT-qPCR was used to quantify miR-382-5p levels in PVAT-EXOs from patients and mice.
- Macrophage lipid accumulation was assessed using oil red O staining.
- Cholesterol uptake, efflux, and the expression of cholesterol transporters (ABCA1, ABCG1) were evaluated following PVAT-EXO treatment and specific molecular interventions.
Main Results:
- miR-382-5p levels were lower in PVAT-EXOs from coronary artery disease patients compared to healthy individuals.
- PVAT-EXOs significantly reduced macrophage foam cell formation and enhanced cholesterol efflux.
- Inhibition of miR-382-5p reversed the beneficial effects of PVAT-EXOs on foam cell formation and cholesterol efflux.
- BMP4-PPARγ signaling was identified as a key pathway mediating the upregulation of ABCA1 and ABCG1 by PVAT-EXOs.
Conclusions:
- PVAT-EXOs exert atheroprotective effects by reducing macrophage foam cell formation.
- The mechanism involves miR-382-5p delivery via EXOs, which, along with BMP4-PPARγ signaling, upregulates ABCA1 and ABCG1 expression, promoting cholesterol efflux.
- These findings highlight PVAT-EXOs as a potential therapeutic target for atherosclerosis prevention and treatment.
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