Aerobic Exercise Reduces Macrophage Inflammation and Lipid Accumulation in Atherosclerosis via Extracellular Vesicle-miR-203a-3p and miR-133b-3p.

Abstract

Aerobic exercise reduces cardiovascular disease risk, with atherosclerosis being a primary contributor. While circulating extracellular vesicles (EVs) mediate intercellular communication, their role in this process remains unclear. This study aimed to investigate the role of aerobic exercise-derived circulating EVs in mitigating macrophage inflammation and lipid accumulation in an atherosclerotic model. Circulating EVs were isolated from the plasma of exercise-trained and sedentary mice. miRNA profiling of EVs was performed using miRNA arrays and quantitative real-time PCR. Aortic atherosclerosis was assessed by Oil Red O staining, immunofluorescence, and ELISA. Functional validation of EV effects was carried out through EVs labeling, cell transfection, luciferase reporter assays, and flow cytometry. Aerobic exercise slowed the progression of atherosclerosis and altered the miRNA profile of circulating EVs, notably increasing miR-203a-3p and miR-133b-3p expression. EVs from exercise-trained mice inhibited macrophage-driven inflammation and lipid accumulation in vitro and in vivo. Treatment with miR-203a-3p and miR-133b-3p mimics reproduced the anti-atherosclerotic effects, while inhibitors of these miRNAs reversed the effects. Mechanistically, miR-203a-3p and miR-133b-3p reduced macrophage inflammation and lipid accumulation by targeting Tlr4 and Insr, respectively, thereby suppressing NF-κB/NLRP3 signaling. Notably, the increased expression of miR-203a-3p and miR-133b-3p was primarily derived from skeletal muscle. These findings highlight a novel mechanism linking aerobic exercise to atherosclerosis via EV-miRNAs, proposing potential therapeutic strategies for atherosclerosis based on exercise-induced circulating EVs-miR-203a-3p and miR-133b-3p.