Overexpression of core 2 N-acetylglycosaminyltransferase enhances cytokineactions and induces hypertrophic myocardium in transgenic mice

Elevated levels of glycocojugates, commonly observed in the myocardium of d iabetic animals and patients, are postulated to contribute to the myocardia l dysfunction in diabetes. Previously, we reported that UDP-GlcNAc: Gal bet a 1-3GalNAc alpha R beta 1-6-N-acetylglucosaminyltransferase (core 2 GlcNAc -T), a developmentally regulated enzyme of O-linked glycans biosynthesis pa thway, is specifically increased in the heart of diabetic animals and Is re gulated by hyperglycemia and insulin. In this study, transgenic mice overex pressing core 2 GlcNAc-T with severe increase in cardiac core 2 GlcNAc-T ac tivities were normal at birth but showed progressive and significant cardia c hypertrophy at 6 months of age. The heart of transgenic mice showed eleva tion of sialylated O-glycan and increases of c-fos gene expression and AP-I activity, which are characteristics of cardiac stress. Furthermore, transf ection of PC12 cells with core 2 GlcNAc-T also induced c-fos promoter activ ation, mitogen activated-protein kinase (MAPK) phosphorylation, Trk recepto r 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.