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Am J Physiol Cell Physiol ; 306(9): C794-804, 2014 May 01.
Article in English | MEDLINE | ID: mdl-24553187

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-ß1 (TGF-ß1), 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.


Subject(s)
Collagen/biosynthesis , Diabetic Cardiomyopathies/metabolism , Fibroblasts/metabolism , Glucose/metabolism , Myocardium/metabolism , Protein Processing, Post-Translational , Acetylglucosaminidase/genetics , Acetylglucosaminidase/metabolism , Animals , Arginase/metabolism , Cells, Cultured , Diabetic Cardiomyopathies/pathology , Fibroblasts/pathology , Glycosylation , Male , Myocardium/pathology , Rats , Rats, Sprague-Dawley , Signal Transduction , Smad Proteins/metabolism , Sp1 Transcription Factor/metabolism , Time Factors , Transfection , Transforming Growth Factor beta1/metabolism , Up-Regulation
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