TY - JOUR
T1 - Role for high-glucose-induced protein O-GlcNAcylation in stimulating cardiac fibroblast collagen synthesis
AU - Aguilar, Hugo
AU - Fricovsky, Eduardo
AU - Ihm, Sang
AU - Schimke, Magdalena
AU - Maya-Ramos, Lisandro
AU - Aroonsakool, Nakon
AU - Ceballos, Guillermo
AU - Dillmann, Wolfgang
AU - Villarreal, Francisco
AU - Ramirez-Sanchez, Israel
PY - 2014/5/1
Y1 - 2014/5/1
N2 - 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.
AB - 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.
KW - Cardiomyopathy
KW - Diabetes
KW - Fibroblast
KW - Fibrosis
KW - Glycosylation
UR - http://www.scopus.com/inward/record.url?scp=84900540044&partnerID=8YFLogxK
U2 - 10.1152/ajpcell.00251.2013
DO - 10.1152/ajpcell.00251.2013
M3 - Artículo
C2 - 24553187
SN - 0363-6143
VL - 306
SP - C794-C804
JO - American Journal of Physiology - Cell Physiology
JF - American Journal of Physiology - Cell Physiology
IS - 9
ER -