O-GlcNAc signaling is essential for NFAT-mediated transcriptional reprogramming during cardiomyocyte hypertrophy.

Academic Article

Abstract

  • The regulation of cardiomyocyte hypertrophy is a complex interplay among many known and unknown processes. One specific pathway involves the phosphatase calcineurin, which regulates nuclear translocation of the essential cardiac hypertrophy transcription factor, nuclear factor of activated T-cells (NFAT). Although metabolic dysregulation is frequently described during cardiac hypertrophy, limited insights exist regarding various accessory pathways. One metabolically derived signal, beta-O-linked N-acetylglucosamine (O-GlcNAc), has emerged as a highly dynamic posttranslational modification of serine and threonine residues regulating physiological and stress processes. Given the metabolic dysregulation during hypertrophy, we hypothesized that NFAT activation is dependent on O-GlcNAc signaling. Pressure overload-induced hypertrophy (via transverse aortic constriction) in mice or treatment of neonatal rat cardiac myocytes with phenylephrine significantly enhanced global O-GlcNAc signaling. NFAT-luciferase reporter activity revealed O-GlcNAc-dependent NFAT activation during hypertrophy. Reversal of enhanced O-GlcNAc signaling blunted cardiomyocyte NFAT-induced changes during hypertrophy. Taken together, these results demonstrate a critical role of O-GlcNAc signaling in NFAT activation during hypertrophy and provide evidence that O-GlcNAc signaling is coordinated with the onset and progression of cardiac hypertrophy. This represents a potentially significant and novel mechanism of cardiac hypertrophy, which may be of particular interest in future in vivo studies of hypertrophy.
  • Keywords

  • Acetylglucosamine, Animals, Cardiomegaly, Cells, Cultured, Male, Mice, Mice, Inbred C57BL, Models, Animal, Myocytes, Cardiac, NFATC Transcription Factors, Phenylephrine, Protein Processing, Post-Translational, Rats, Rats, Sprague-Dawley, Signal Transduction, Transcription, Genetic
  • Digital Object Identifier (doi)

    Author List

  • Facundo HT; Brainard RE; Watson LJ; Ngoh GA; Hamid T; Prabhu SD; Jones SP
  • Start Page

  • H2122
  • End Page

  • H2130
  • Volume

  • 302
  • Issue

  • 10