Molecular mechanisms mediating cardiac hypertrophy by glucose metabolism are incompletely understood. Hexosamine biosynthesis pathway (HBP), an accessory pathway of glycolysis, is known to be involved in the attachment of O-linked N-acetylglucosamine motif (O-GlcNAcylation) to proteins, a post-translational modification. We here demonstrate that glutamine-fructose-6-phosphate amidotransferase 2 (GFAT2), a critical HBP enzyme, is a major isoform of GFAT in the heart and is increased in response to several hypertrophic stimuli, including isoproterenol (ISO). Knockdown of GFAT2 suppresses ISO-induced cardiomyocyte hypertrophy, accompanied by suppression of Akt O-GlcNAcylation and activation. Knockdown of GFAT2 does not affect anti-hypertrophic effect by Akt inhibition. Administration of glucosamine, a substrate of HBP, induces protein O-GlcNAcylation, Akt activation, and cardiomyocyte hypertrophy. In mice, 6-diazo-5-oxo-L-norleucine, an inhibitor of GFAT, attenuates ISO-induced protein O-GlcNAcylation, Akt activation, and cardiac hypertrophy. Our results demonstrate that GFAT2 mediates cardiomyocyte hypertrophy by HBP-O-GlcNAcylation-Akt pathway and could be a critical therapeutic target of cardiac hypertrophy.
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