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

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.