Impaired intracellular calcium homeostasis enhances protein O-GlcNAcylation and promotes vascular calcification and stiffness in diabetes

mice. Inhibition of O-GlcNAcylation with a pharmacological inhibitor abolished STIM1 deficiency-induced VSMC calcification, supporting a critical role of O-GlcNAcylation in mediating STIM1 deficiency-induced VSMC calcification. Mechanistically, we identified that STIM1 deficiency resulted in impaired calcium homeostasis, which activated calcium signaling and increased endoplasmic reticulum (ER) stress in VSMC, while inhibition of ER stress attenuated STIM1-induced elevation of protein O-GlcNAcylation. In conclusion, the study has demonstrated a causative role of SMC-expressed STIM1 in regulating vascular calcification and stiffness in diabetes. We have further identified a novel mechanisms underlying STIM1 deficiency-induced impairment of calcium homeostasis and ER stress in upregulation of protein O-GlcNAcylation in VSMC, which promotes VSMC osteogenic differentiation and calcification in diabetes.