Role for high-glucose-induced protein O-GlcNAcylation in stimulating cardiac fibroblast collagen synthesis

Hugo Aguilar, Eduardo Fricovsky, Sang Ihm, Magdalena Schimke, Lisandro Maya-Ramos, Nakon Aroonsakool, Guillermo Ceballos, Wolfgang Dillmann, Francisco Villarreal, Israel Ramirez-Sanchez

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

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 OGlcNAc moieties from proteins, decreased Sp1 and arginase II OGlcNAcylation 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.

Original languageEnglish
Pages (from-to)C794-C804
JournalAmerican Journal of Physiology - Cell Physiology
Volume306
Issue number9
DOIs
StatePublished - 1 May 2014

Keywords

  • Cardiomyopathy
  • Diabetes
  • Fibroblast
  • Fibrosis
  • Glycosylation

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