title: Activation of AKT by O-linked N-acetylglucosamine induces vascular calcification in diabetes mellitus.
abstract: BACKGROUND
  Vascular calcification is a serious cardiovascular complication that contributes to the increased morbidity and mortality of patients with diabetes mellitus. Hyperglycemia, a hallmark of diabetes mellitus, is associated with increased vascular calcification and increased modification of proteins by O-linked N-acetylglucosamine (O-GlcNAcylation).
  
  
  OBJECTIVE
  We sought to determine the role of protein O-GlcNAcylation in regulating vascular calcification and the underlying mechanisms.
  
  
  RESULTS
  Low-dose streptozotocin-induced diabetic mice exhibited increased aortic O-GlcNAcylation and vascular calcification, which was also associated with impaired aortic compliance in mice. Elevation of O-GlcNAcylation by administration of Thiamet-G, a potent inhibitor for O-GlcNAcase that removes O-GlcNAcylation, further accelerated vascular calcification and worsened aortic compliance of diabetic mice in vivo. Increased O-GlcNAcylation, either by Thiamet-G or O-GlcNAcase knockdown, promoted calcification of primary mouse vascular smooth muscle cells. Increased O-GlcNAcylation in diabetic arteries or in the O-GlcNAcase knockdown vascular smooth muscle cell upregulated expression of the osteogenic transcription factor Runx2 and enhanced activation of AKT. O-GlcNAcylation of AKT at two new sites, T430 and T479, promoted AKT phosphorylation, which in turn enhanced vascular smooth muscle cell calcification. Site-directed mutation of AKT at T430 and T479 decreased O-GlcNAcylation, inhibited phosphorylation of AKT at S473 and binding of mammalian target of rapamycin complex 2 to AKT, and subsequently blocked Runx2 transactivity and vascular smooth muscle cell calcification.
  
  
  CONCLUSIONS
  O-GlcNAcylation of AKT at 2 new sites enhanced AKT phosphorylation and activation, thus promoting vascular calcification. Our studies have identified a novel causative effect of O-GlcNAcylation in regulating vascular calcification in diabetes mellitus and uncovered a key molecular mechanism underlying O-GlcNAcylation-mediated activation of AKT.
authors: From the Departments of Pathology (J.M.H., Y.S., K.Y., S.L., J.C.C., Y.C.), Medicine (W.E.B., L.J.D'I.), and Pediatric Dentistry (H.W.), University of Alabama at Birmingham; and Veterans Affairs, Department of Research Service, Birmingham, AL (L.J.D'I., Y.C.).
authors: Jack M
authors: JM
authors: Heath
authors: Yong
authors: Y
authors: Sun
authors: Kaiyu
authors: K
authors: Yuan
authors: Wayne E
authors: WE
authors: Bradley
authors: Silvio
authors: S
authors: Litovsky
authors: Louis J
authors: LJ
authors: Dell'Italia
authors: John C
authors: JC
authors: Chatham
authors: Hui
authors: H
authors: Wu
authors: Yabing
authors: Y
authors: Chen
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology*; D006031:Glycosylation; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011714:Pyrans / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D061205:Vascular Calcification / Q000378:metabolism* / Q000473:pathology; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D046912:Multiprotein Complexes; D011714:Pyrans; D013844:Thiazoles; C572247:thiamet G; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases; D000117:Acetylglucosamine
keywords: diabetes mellitus; myocytes, smooth muscle; vascular calcification