O-GlcNAc signaling attenuates ER stress-induced cardiomyocyte death.

Academic Article

Abstract

  • We previously demonstrated that the O-linked beta-N-acetylglucosamine (O-GlcNAc) posttranslational modification confers cardioprotection at least partially through mitochondrial-dependent mechanisms, but it remained unclear if O-GlcNAc signaling interfered with other mechanisms of cell death. Because ischemia/hypoxia causes endoplasmic reticulum (ER) stress, we ascertained whether O-GlcNAc signaling could attenuate ER stress-induced cell death per se. Before induction of ER stress (with tunicamycin or brefeldin A), we adenovirally overexpressed O-GlcNAc transferase (AdOGT) or pharmacologically inhibited O-GlcNAcase [via O-(2-acetamido-2-deoxy-d-glucopyranosylidene) amino-N-phenylcarbamate] to augment O-GlcNAc levels or adenovirally overexpressed O-GlcNAcase to reduce O-GlcNAc levels. AdOGT significantly (P < 0.05) attenuated the activation of the maladaptive arm of the unfolded protein response [according to C/EBP homologous protein (CHOP) activation] and cardiomyocyte death (reflected by percent propidium iodide positivity). Moreover, pharmacological inhibition of O-GlcNAcase significantly (P < 0.05) mitigated ER stress-induced CHOP activation and cardiac myocyte death. Interestingly, overexpression of GCA did not alter ER stress markers but exacerbated brefeldin A-induced cardiomyocyte death. We conclude that enhanced O-GlcNAc signaling represents a partially proadaptive response to reduce ER stress-induced cell death. These results provide new insights into a possible interaction between O-GlcNAc signaling and ER stress and may partially explain a mechanism of O-GlcNAc-mediated cardioprotection.
  • Keywords

  • Acetylglucosamine, Adaptation, Physiological, Animals, Animals, Newborn, Brefeldin A, Cell Death, Cell Hypoxia, Cells, Cultured, Cytoprotection, Endoplasmic Reticulum, Enzyme Inhibitors, Myocardial Reperfusion Injury, Myocytes, Cardiac, N-Acetylglucosaminyltransferases, Oximes, Phenylcarbamates, Rats, Rats, Sprague-Dawley, Signal Transduction, Stress, Physiological, Transcription Factor CHOP, Transfection, Tunicamycin, beta-N-Acetylhexosaminidases
  • Digital Object Identifier (doi)

    Author List

  • Ngoh GA; Hamid T; Prabhu SD; Jones SP
  • Start Page

  • H1711
  • End Page

  • H1719
  • Volume

  • 297
  • Issue

  • 5