O-Glycosylation Regulates Ubiquitination and Degradation of the Anti-Inflammatory Protein A20 to Accelerate Atherosclerosis in Diabetic ApoE-Null Mice

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O-Glycosylation Regulates Ubiquitination and Degradation of the Anti-Inflammatory Protein A20 to Accelerate Atherosclerosis in Diabetic ApoE-Null Mice

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dc.contributor.author Shrikhande, Gautam V.
dc.contributor.author Scali, Salvatore T.
dc.contributor.author Csizmadia, Eva
dc.contributor.author Matthey, Michaela
dc.contributor.author Arjoon, Roy
dc.contributor.author Patel, Rakesh
dc.contributor.author Maccariello, Elizabeth R.
dc.contributor.author Andersen, Nicholas D.
dc.contributor.author Monahan, Thomas
dc.contributor.author Studer, Peter
dc.contributor.author Padilha Guedes, Renata
dc.contributor.author Usheva, Anny
dc.contributor.author Da Silva, Cleide Gonsalves
dc.contributor.author Damrauer, Scott Michael
dc.contributor.author Putheti, Prabhakar
dc.contributor.author Siracuse, Jeffrey Joseph
dc.contributor.author Peterson, Clayton Ross
dc.contributor.author Essayagh, Sanah
dc.contributor.author Kocher, Olivier Nicolas
dc.contributor.author Veves, Aristidis
dc.contributor.author Kaczmarek, Elzbieta
dc.contributor.author Ferran, Christiane
dc.date.accessioned 2011-11-09T17:48:24Z
dc.date.issued 2010
dc.identifier.citation Shrikhande, Gautam V., Salvatore T. Scali, Cleide G. da Silva, Scott M. Damrauer, Eva Csizmadia, Prabhakar Putheti, Michaela Matthey, et al. 2010. O-Glycosylation Regulates Ubiquitination and Degradation of the Anti-Inflammatory Protein A20 to Accelerate Atherosclerosis in Diabetic ApoE-Null Mice. PLoS ONE 5(12): e14240. en_US
dc.identifier.issn 1932-6203 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:5343537
dc.description.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. Methodology/Principal Findings: 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. en_US
dc.language.iso en_US en_US
dc.publisher Public Library of Science en_US
dc.relation.isversionof doi:10.1371/journal.pone.0014240 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2997780/pdf/ en_US
dash.license LAA
dc.subject cardiovascular disorders en_US
dc.subject vascular biology en_US
dc.subject diabetes and endocrinology en_US
dc.subject type 2 diabetes en_US
dc.subject type 1 diabetes en_US
dc.subject pathology en_US
dc.subject surgical pathology en_US
dc.title O-Glycosylation Regulates Ubiquitination and Degradation of the Anti-Inflammatory Protein A20 to Accelerate Atherosclerosis in Diabetic ApoE-Null Mice en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal PLoS ONE en_US
dash.depositing.author Putheti, Prabhakar
dc.date.available 2011-11-09T17:48:24Z
dash.affiliation.other HMS^Medicine- Beth Israel-Deaconess en_US
dash.affiliation.other HMS^Pathology en_US
dash.affiliation.other HMS^Surgery- Beth Israel-Deaconess en_US

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