Deletion of Smooth Muscle O-GlcNAc Transferase Prevents Development of Atherosclerosis in Western Diet-Fed Hyperglycemic ApoE(-/-) Mice In Vivo

Accumulating evidence highlights protein O-GlcNAcylation as a putative pathogenic contributor of diabetic vascular complications. We previously reported that elevated protein O-GlcNAcylation correlates with increased atherosclerotic lesion formation and VSMC proliferation in response to hyperglycemia. However, the role of O-GlcNAc transferase (OGT), regulator of O-GlcNAc signaling, in the evolution of diabetic atherosclerosis remains elusive. The goal of this study was to determine whether smooth muscle OGT (smOGT) plays a direct role in hyperglycemia-induced atherosclerotic lesion formation and SMC de-differentiation. Using tamoxifen-inducible Myh11-CreER(T2) and Ogt(fl/fl) mice, we generated smOGT(WT) and smOGT(KO) mice, with and without ApoE-null backgrounds. Following STZ-induced hyperglycemia, smOGT(WT) and smOGT(KO) mice were kept on a standard laboratory diet for the study duration. In a parallel study, smOGT(WT)ApoE(-/-) and smOGT(KO)ApoE(-/-) were initiated on Western diet at 8-wks-age. Animals harvested at 14–16-wks-age were used for plasma and tissue collection. Loss of smOGT augmented SM contractile marker expression in aortic vessels of STZ-induced hyperglycemic smOGT(KO) mice. Consistently, smOGT deletion attenuated atherosclerotic lesion lipid burden (Oil red O), plaque area (H&E), leukocyte (CD45) and smooth muscle cell (ACTA2) abundance in Western diet-fed hyperglycemic smOGT(KO)ApoE(-/-) mice. This was accompanied by increased SM contractile markers and reduced inflammatory and proliferative marker expression. Further, smOGT deletion attenuated YY1 and SRF expression (transcriptional regulators of SM contractile genes) in hyperglycemic smOGT(KO)ApoE(-/-) and smOGT(KO) mice. These data uncover an athero-protective outcome of smOGT loss-of-function and suggest a direct regulatory role of OGT-mediated O-GlcNAcylation in VSMC de-differentiation in hyperglycemia.