Inhibiting AIDA suppresses VSMC-derived foam cell formation and atherosclerosis by hindering CD36 membrane translocation

Vascular smooth muscle cell (VSMC)-derived foam cells critically drive atherosclerotic plaque progression, yet their regulatory mechanisms remain incompletely understood. This study aimed to elucidate the pathophysiological role of the VSMC-enriched factor axin interactor, dorsalization-associated (AIDA) in this process and evaluate its therapeutic potential. We utilized VSMC-specific AIDA knockout in male ApoE -/- mice and adenoviral shRNA silencing in oxLDL-stimulated murine aortic vascular smooth muscle cells (MOVAS), combined with co-immunoprecipitation (Co-IP), cholesterol flux assays, and ubiquitination profiling, which revealed that AIDA is selectively upregulated in VSMCs within human and murine atherosclerotic plaques. AIDA knockout attenuated aortic plaque burden, fibrosis, and elastic fiber fragmentation in vivo, and suppressed oxidized low-density lipoprotein (oxLDL) uptake and foam cell formation in vitro by specifically impairing CD36 membrane trafficking without affecting cholesterol efflux. Mechanistically, AIDA scaffolds HMG-CoA reductase degradation protein 1 (HRD1)-mediated K63-linked ubiquitination of vesicle-associated membrane protein 3 (VAMP3), resulting in the VAMP3-CD36 interaction and subsequent CD36 membrane translocation. These results demonstrate that AIDA promotes VSMC-derived foam cell formation by facilitating CD36 trafficking through the HRD1-VAMP3 ubiquitination axis, identifying the AIDA-HRD1-VAMP3-CD36 pathway as a potential novel strategy for the treatment of atherosclerosis.