title: O-glycosylation regulates ubiquitination and degradation of the anti-inflammatory protein A20 to accelerate atherosclerosis in diabetic ApoE-null mice.
abstract: BACKGROUND
  Accelerated atherosclerosis is the leading cause of morbidity and mortality in diabetic patients. Hyperglycemia is a recognized independent risk factor for heightened atherogenesis in diabetes mellitus (DM). However, our understanding of the mechanisms underlying glucose damage to the vasculature remains incomplete.
  
  
  RESULTS
  High glucose and hyperglycemia reduced upregulation of the NF-κB inhibitory and atheroprotective protein A20 in human coronary endothelial (EC) and smooth muscle cell (SMC) cultures challenged with Tumor Necrosis Factor alpha (TNF), aortae of diabetic mice following Lipopolysaccharide (LPS) injection used as an inflammatory insult and in failed vein-grafts of diabetic patients. Decreased vascular expression of A20 did not relate to defective transcription, as A20 mRNA levels were similar or even higher in EC/SMC cultured in high glucose, in vessels of diabetic C57BL/6 and FBV/N mice, and in failed vein grafts of diabetic patients, when compared to controls. Rather, decreased A20 expression correlated with post-translational O-Glucosamine-N-Acetylation (O-GlcNAcylation) and ubiquitination of A20, targeting it for proteasomal degradation. Restoring A20 levels by inhibiting O-GlcNAcylation, blocking proteasome activity, or overexpressing A20, blocked upregulation of the receptor for advanced glycation end-products (RAGE) and phosphorylation of PKCβII, two prime atherogenic signals triggered by high glucose in EC/SMC. A20 gene transfer to the aortic arch of diabetic ApoE null mice that develop accelerated atherosclerosis, attenuated vascular expression of RAGE and phospho-PKCβII, significantly reducing atherosclerosis.
  
  
  CONCLUSIONS
  High glucose/hyperglycemia regulate vascular A20 expression via O-GlcNAcylation-dependent ubiquitination and proteasomal degradation. This could be key to the pathogenesis of accelerated atherosclerosis in diabetes.
authors.affiliation: The Division of Vascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Gautam V
authors.initials: GV
authors.lastname: Shrikhande
authors.forename: Salvatore T
authors.initials: ST
authors.lastname: Scali
authors.forename: Cleide G
authors.initials: CG
authors.lastname: da Silva
authors.forename: Scott M
authors.initials: SM
authors.lastname: Damrauer
authors.forename: Eva
authors.initials: E
authors.lastname: Csizmadia
authors.forename: Prabhakar
authors.initials: P
authors.lastname: Putheti
authors.forename: Michaela
authors.initials: M
authors.lastname: Matthey
authors.forename: Roy
authors.initials: R
authors.lastname: Arjoon
authors.forename: Rakesh
authors.initials: R
authors.lastname: Patel
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Siracuse
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Maccariello
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Andersen
authors.forename: Thomas
authors.initials: T
authors.lastname: Monahan
authors.forename: Clayton
authors.initials: C
authors.lastname: Peterson
authors.forename: Sanah
authors.initials: S
authors.lastname: Essayagh
authors.forename: Peter
authors.initials: P
authors.lastname: Studer
authors.forename: Renata Padilha
authors.initials: RP
authors.lastname: Guedes
authors.forename: Olivier
authors.initials: O
authors.lastname: Kocher
authors.forename: Anny
authors.initials: A
authors.lastname: Usheva
authors.forename: Aristidis
authors.initials: A
authors.lastname: Veves
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Kaczmarek
authors.forename: Christiane
authors.initials: C
authors.lastname: Ferran
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D006031:Glycosylation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D016328:NF-kappa B / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D025801:Ubiquitin / Q000737:chemistry*
chemical_list: D001057:Apolipoproteins E; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D025801:Ubiquitin; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse