ATP6V0D2 Promotes Atherosclerosis‐Associated Vascular Smooth Muscle Cell Dysfunction by Modulating Ferroptosis‐Related Signaling

Abstract

ABSTRACT Background Atherosclerosis (AS) underlies a substantial proportion of cardiovascular morbidity and mortality, yet the molecular events that drive vascular cell injury remain only partly resolved. Methods We first compared aortic transcriptomes from apolipoprotein E‐deficient (ApoE−/−) mice maintained on control or high‐fat diets. Candidate‐gene effects were then examined in human vascular smooth muscle cells (HVSMCs) challenged with oxidized low‐density lipoprotein (ox‐LDL). Results The aortic dataset contained 2832 differentially expressed genes (1800 increased and 1032 decreased). Of the five genes taken forward, ATP6V0D2 displayed a graded increase as the ox‐LDL concentration rose. Network and enrichment results connected ATP6V0D2 to proton movement, acidification of intracellular organelles, and iron transport. Silencing ATP6V0D2 limited the ox‐LDL‐evoked accumulation of neutral lipid and restrained cell‐cycle entry, motility, and invasion. At the molecular level, knockdown lowered acyl‐CoA synthetase long‐chain family member 4 (ACSL4) and recovered solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4). It also raised glutathione (GSH) abundance and superoxide dismutase (SOD) activity while decreasing malondialdehyde (MDA), reactive oxygen species (ROS), mitochondrial contraction, and cristae damage. Ferrostatin‐1 shifted the molecular, redox, and ultrastructural readouts in the same direction. Conclusions These data identify ATP6V0D2 as a contributor to the abnormal HVSMC phenotypes produced by ox‐LDL. Its depletion appears to blunt this response, in part through attenuation of changes compatible with ferroptosis and warrants further evaluation as a mechanistic target for AS.