Abstract
Atherosclerosis is a leading cause of cardiovascular morbidity and mortality, yet the molecular mechanisms driving plaque progression remain incompletely understood. O-GlcNAc transferase (OGT) couples nutrient status to protein O-GlcNAcylation, but its vascular actions appear context dependent. In an exploratory carotid endarterectomy cohort, OGT expression and global O-GlcNAcylation were higher in plaques obtained from symptomatic patients than in plaques from asymptomatic patients. In Western diet-fed ApoE-/- mice, inducible smooth muscle cell (SMC)-specific OGT deletion was associated with lower aortic lesion burden, lower serum triglyceride and total cholesterol concentrations, and reduced plaque lipid and collagen areas. Proteomic screening identified TEAD1 as an O-GlcNAcylated protein enriched in clinically symptomatic human samples. OGT interacted with TEAD1 and promoted O-GlcNAcylation at Serine 132 (S132); mutation of this residue reduced TEAD1 stability, nuclear accumulation, and reporter activity. In a complementary HUVEC model, OGT knockdown limited ox-LDL-induced injury, inflammation, monocyte adhesion, and endothelial-to-mesenchymal transition, whereas TEAD1 overexpression attenuated these effects. Smooth muscle-targeted TEAD1 overexpression also attenuated the lesion reduction associated with OGT deletion in vivo. These findings support an OGT-TEAD1 pathway in atherosclerosis while indicating that concurrent lipid changes, plaque-cell specificity, and the relative endothelial contribution require further resolution.