title: Role for high-glucose-induced protein O-GlcNAcylation in stimulating cardiac fibroblast collagen synthesis.
abstract: Excess enzyme-mediated protein O-GlcNAcylation is known to occur with diabetes mellitus. A characteristic of diabetic cardiomyopathy is the development of myocardial fibrosis. The role that enhanced protein O-GlcNAcylation plays in modulating the phenotype of cardiac fibroblasts (CF) is unknown. To address this issue, rat CF were cultured in normal glucose (NG; 5 mM glucose) or high-glucose (HG; 25 mM) media for 48 h. Results demonstrate that CF cultured in HG have higher levels (~50%) of overall protein O-GlcNAcylation vs. NG cells. Key regulators of collagen synthesis such as transforming-growth factor-β1 (TGF-β1), SMADs 2/3, and SMAD 7 protein levels, including those of arginase I and II, were altered, leading to increases in collagen levels. The nuclear transcription factor Sp1 and arginase II evidence excess O-GlcNAcylation in HG cells. Expression in CF of an adenovirus coding for the enzyme N-acetylglucosaminidase, which removes O-GlcNAc moieties from proteins, decreased Sp1 and arginase II O-GlcNAcylation and restored HG-induced perturbations in CF back to NG levels. These findings may have important pathophysiological implications for the development of diabetes-induced cardiac fibrosis.
authors.affiliation: Seccion de Posgrado, Escuela Superior de Medicina, Instituto Politecnico Nacional, Ciudad de Mexico, Mexico.
authors.forename: Hugo
authors.initials: H
authors.lastname: Aguilar
authors.forename: Eduardo
authors.initials: E
authors.lastname: Fricovsky
authors.forename: Sang
authors.initials: S
authors.lastname: Ihm
authors.forename: Magdalena
authors.initials: M
authors.lastname: Schimke
authors.forename: Lisandro
authors.initials: L
authors.lastname: Maya-Ramos
authors.forename: Nakon
authors.initials: N
authors.lastname: Aroonsakool
authors.forename: Guillermo
authors.initials: G
authors.lastname: Ceballos
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dillmann
authors.forename: Francisco
authors.initials: F
authors.lastname: Villarreal
authors.forename: Israel
authors.initials: I
authors.lastname: Ramirez-Sanchez
mesh_terms: D000118:Acetylglucosaminidase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001119:Arginase / Q000378:metabolism; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis*; D058065:Diabetic Cardiomyopathies / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000378:metabolism*; D006031:Glycosylation; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D011499:Protein Processing, Post-Translational; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D051785:Smad Proteins; D016329:Sp1 Transcription Factor; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D003094:Collagen; D000118:Acetylglucosaminidase; C113162:Arg2 protein, rat; D001119:Arginase; C542908:arginase I, rat; D005947:Glucose
keywords: cardiomyopathy; diabetes; fibroblast; fibrosis; glycosylation