title: Protein modification by O-linked GlcNAc reduces angiogenesis by inhibiting Akt activity in endothelial cells.
abstract: OBJECTIVE
  Glucose flux through the hexosamine biosynthesis pathway (HBP) has been implicated in the development of diabetic vascular complications. O-linked N-acetylglucosamine (O-GlcNAc) modification on protein is the major mechanism mediating the actions of the HBP. Impaired angiogenesis is well-recognized in diabetes; however, the mechanisms are not completely defined. Here, we investigated the role of protein O-GlcNAc modification in angiogenesis.
  
  
  RESULTS
  In a mouse aortic ring assay, elevated O-GlcNAc levels induced by high-fat diet, streptozotocin-induced diabetes, or in vitro glucosamine treatment were associated with impaired angiogenesis. In cultured human umbilical vein endothelial cells and EA.hy926 endothelial cells, glucosamine increased protein O-GlcNAc modification and inhibited cell migration and capillary-like structure formation. Conversely, removal of O-GlcNAc by adenoviral-mediated overexpression of O-GlcNAcase improved these steps of angiogenesis. Also, high concentrations of glucose reduced capillary-like structure formation of human umbilical vein endothelial cells. Akt was recognized by an O-GlcNAc specific lectin, and glucosamine increased the amounts of Akt protein in these lectin precipitates. Increased glycosylation paralleled reduced Akt activity in endothelial cells.
  
  
  CONCLUSIONS
  These results suggest that elevated protein O-GlcNAc modification through the HBP impairs angiogenesis in endothelial cells, possibly by inhibiting Akt signaling.
authors.affiliation: Division of Endocrinology, University of Utah, Salt Lake City, UT 84132, USA.
authors.forename: Bai
authors.initials: B
authors.lastname: Luo
authors.forename: Yudi
authors.initials: Y
authors.lastname: Soesanto
authors.forename: Donald A
authors.initials: DA
authors.lastname: McClain
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology; D002196:Capillaries / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D003925:Diabetic Angiopathies / Q000378:metabolism* / Q000473:pathology*; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005947:Glucose / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D046509:Tissue Culture Techniques
chemical_list: D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose; D000117:Acetylglucosamine