Fine particulate matter contributes to the development of atherosclerosis via miR-3529–3p encapsulated in extracellular vesicles

Exposure to fine particulate matter (PM_2.5) has been closely correlated with cardiovascular morbidity and mortality. The present study elucidates the mechanism by which PM_2.5 induces vascular endothelial injury and accelerates atherosclerosis through alveolar macrophage-derived extracellular vesicles (AMs-EVs). Utilizing ApoE^-/- mice and in vitro models, it was demonstrated that PM_2.5 exposure provokes pulmonary inflammation and M1 macrophage polarization, thereby augmenting the release of AMs-EVs. These EVs traverse the alveolar-capillary barrier into the systemic circulation and are internalized by vascular endothelial cells, thereby aggravating aortic plaque formation and endothelial dysfunction. Mechanistically, PM_2.5-EVs downregulate the expression of ferritin heavy chain 1 (FTH1) in endothelial cells by delivering miR-3529-3p, a microRNA enriched in PM_2.5-EVs. This suppression disrupts iron homeostasis, culminating in iron overload, lipid peroxidation, and mitochondrial damage-hallmarks of ferroptosis. Inhibition of EV release (via GW4869) or ferroptosis (via ferrostatin-1) significantly mitigated PM_2.5-induced endothelial injury. Additionally, dual-luciferase reporter assays verified that miR-3529-3p directly targets the 3'-UTR of FTH1 mRNA, thereby establishing a causal link between the miR-3529-3p/FTH1 axis and ferroptosis-driven atherosclerosis. The findings reveal a novel intercellular communication mechanism through which PM_2.5 primes macrophages to release EVs carrying miR-3529-3p, thereby promoting endothelial ferroptosis and the progression of atherosclerosis. This study offers critical insights into the involvement of EVs in pollutant-related cardiovascular pathogenesis and identifies FTH1 as a promising therapeutic target.