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

Exposure to fine particulate matter (PM) has been closely correlated with cardiovascular morbidity and mortality. The present study elucidates the mechanism by which PM 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 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-EVs downregulate the expression of ferritin heavy chain 1 (FTH1) in endothelial cells by delivering miR-3529-3p, a microRNA enriched in PM-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-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 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.