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* Research Division, Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts 02215, USA;
Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02215 USA; and
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada M5G 1X5
1Correspondence: Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail: Kingg{at}joslab.harvard.edu
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: Galß1–3GalNAc
Rß1–6-N-acetylglucosaminyltransferase
(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.
Key Words: O-linked glycans • diabetes • cardiac hypertrophy • MAP kinase activation
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