OGT deficiency in vascular smooth muscle orchestrates foam cell formation and PANoptosis during atherosclerotic progression.

Abstract

BACKGROUND AND AIMS: Vascular smooth muscle cells (VSMCs) contribute to atherosclerotic foam cell formation, but mechanisms regulating their phenotypic switching and programmed cell death remain unclear. O-GlcNAcylation, a nutrient-sensitive post-translational modification implicated in vascular calcification, lacks defined roles in VSMC foam cell biology. METHODS: Inducible smooth muscle-specific Ogt knockout mice on an Apoebackground were subjected to streptozotocin-induced hyperglycemia and a 12-week high-fat/high-cholesterol diet. Immunostaining of aortic sections was performed to evaluate the expression and localization of OGT, O-GlcNAc, and α-SMA in VSMCs and their derived foam cells. Primary VSMCs were treated with oxidized LDL to induce foam cell formation, and OGT inhibition was achieved either pharmacologically using OSMI-1 or genetically via shOgt adenovirus infection. Lipid accumulation was assessed by BODIPY/Oil Red O staining, and cell death was evaluated via TUNEL assay, flow cytometry, and Western blot. RESULTS: OGT expression and global O-GlcNAcylation were reduced in VSMCs during atherogenic progression. Ogt deletion in VSMCs promoted foam cell formation with enhanced lipid accumulation but paradoxically reduced atherosclerotic lesion area concurrent with increased intraplaque cell death. Both genetic and pharmacological OGT inhibition recapitulated this duality in vitro, simultaneously accelerating lipid accumulation while triggering PANoptosis, as evidenced by concurrent activation of cleaved caspase-3, phosphorylated MLKL, and cleaved GSDMD. Individual inhibition of apoptosis, necroptosis, or pyroptosis provided only partial rescue. CONCLUSIONS: OGT acts as a dual regulator of VSMC fate, attenuating plaque burden through PANoptosis induction while promoting foam cell formation, revealing its complex role in atherosclerosis pathogenesis and suggesting context-dependent therapeutic implications.