title: Overexpression of core 2 N-acetylglycosaminyltransferase enhances cytokine actions and induces hypertrophic myocardium in transgenic mice.
abstract: Elevated levels of glycocojugates, commonly observed in the myocardium of diabetic animals and patients, are postulated to contribute to the myocardial dysfunction in diabetes. Previously, we reported that UDP-GlcNAc: Galbeta1-3GalNAcalphaRbeta1-6-N-acetylglucosaminyltransferas e (core 2 GlcNAc-T), a developmentally regulated enzyme of O-linked glycans biosynthesis pathway, is specifically increased in the heart of diabetic animals and is regulated by hyperglycemia and insulin. In this study, transgenic mice overexpressing core 2 GlcNAc-T with severe increase in cardiac core 2 GlcNAc-T activities were normal at birth but showed progressive and significant cardiac hypertrophy at 6 months of age. The heart of transgenic mice showed elevation of sialylated O-glycan and increases of c-fos gene expression and AP-1 activity, which are characteristics of cardiac stress. Furthermore, transfection of PC12 cells with core 2 GlcNAc-T also induced c-fos promoter activation, mitogen activated-protein kinase (MAPK) phosphorylation, Trk receptor glycosylation, and cell differentiation. These results suggested a novel role for core 2 GlcNAc-T in the development of diabetic cardiomyopathy and modulation of the MAP kinase pathway in the heart.-Koya, D., Dennis, J. W., Warren, C. E., Takahara, N., Schoen, F. J., Nishio, Y., Nakajima, T., Lipes, M. A., King, G. L. Overexpression of core 2 N-acetylglycosaminyltransferase enhances cytokine actions and induces hypertrophic myocardium in transgenic mice.
authors.affiliation: Research Division, Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: D
authors.initials: D
authors.lastname: Koya
authors.forename: J W
authors.initials: JW
authors.lastname: Dennis
authors.forename: C E
authors.initials: CE
authors.lastname: Warren
authors.forename: N
authors.initials: N
authors.lastname: Takahara
authors.forename: F J
authors.initials: FJ
authors.lastname: Schoen
authors.forename: Y
authors.initials: Y
authors.lastname: Nishio
authors.forename: T
authors.initials: T
authors.lastname: Nakajima
authors.forename: M A
authors.initials: MA
authors.lastname: Lipes
authors.forename: G L
authors.initials: GL
authors.lastname: King
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism; D016207:Cytokines / Q000502:physiology*; D006031:Glycosylation; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D017351:N-Acetylglucosaminyltransferases / Q000096:biosynthesis / Q000502:physiology*; D016716:PC12 Cells; D011134:Polysaccharides / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection
chemical_list: D016207:Cytokines; D011134:Polysaccharides; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D017351:N-Acetylglucosaminyltransferases; C053024:beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-acetylglucosaminyl transferase; D020917:Receptor, trkA