PM2.5 promotes the phenotypic transition of vascular smooth muscle cells in atherosclerosis by activating pro-ferroptotic signaling via DRP1/PINK1/Parkin-dependent mitophagy

Fine particulate matter (PM2.5), as a widespread environmental pollutant, is closely associated with cardiovascular diseases. The adverse effects of PM2.5 on the cardiovascular system and the molecular mechanisms driving PM2.5-aggravated atherosclerosis remain incompletely understood. In this study, in vivo and in vitro PM2.5 exposure models were established to explore the relevant pathogenic mechanisms. Male ApoE-/-mice were randomly divided into three groups: filtered air(FA) group, unfiltered air(UA) group, and concentrated PM2.5 air(CA) group. For in vitro experiments, mouse aortic vascular smooth muscle cells were exposed to PM2.5 at concentrations of 0, 25, 50, and 100 μg/ml, meanwhile,group control was set up, DRP1 inhibitor Mdivi-1 and ferroptosis inhibitor Fer-1 were used to intervention, and PINK1 knockdown cell model was constructed. Aortic vascular function was evaluated via ultrasonography after exposure. Histopathological changes, collagen deposition, and lipid accumulation in arterial tissues and cells were evaluated via HE staining, Masson staining, Oil Red O, and BODIPY staining, respectively. Immunofluorescence and Western blot were applied to analyze the expression of related proteins in the arterial wall. The results demonstrated that PM2.5 exposure accelerated atherosclerosis progression and VSMC phenotypic switching.PM2.5 exposure upregulated mitochondrial fission proteins and downregulated fusion proteins, with DRP-1 as a critical regulatory molecule. PM2.5 specifically activated PINK1/Parkin-mediated mitophagy rather than the FUNDC1 pathway. PINK1 knockdown markedly attenuated pro-ferroptotic signaling. Mdivi-1 intervention alleviated PM2.5-induced excessive mitophagy, upregulated pro-ferroptotic signaling and phenotypic switching of VSMC. Fer-1 treatment also efficiently inhibited VSMC phenotypic switching.The results of this study demonstrate that DRP1-driven PINK1/Parkin- mediated mitophagy and inducing pro-ferroptotic signaling to promote the phenotypic switching of VSMCs in PM2.5-aggravated atherosclerosis, These findings provide new insights into the pathogenesis of environmental atherosclerosis and potential targets for therapeutic intervention.