O-GlcNAc signaling attenuates ER stress-induced cardiomyocyte death

Am J Physiol Heart Circ Physiol. 2009 Nov;297(5):H1711-9. doi: 10.1152/ajpheart.00553.2009. Epub 2009 Sep 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylglucosamine / analogs & derivatives
  • Acetylglucosamine / metabolism*
  • Acetylglucosamine / pharmacology
  • Adaptation, Physiological
  • Animals
  • Animals, Newborn
  • Brefeldin A / pharmacology
  • Cell Death
  • Cell Hypoxia
  • Cells, Cultured
  • Cytoprotection
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum / pathology
  • Enzyme Inhibitors / pharmacology
  • Myocardial Reperfusion Injury / metabolism*
  • Myocardial Reperfusion Injury / pathology
  • Myocardial Reperfusion Injury / prevention & control
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • N-Acetylglucosaminyltransferases / genetics
  • N-Acetylglucosaminyltransferases / metabolism
  • Oximes / pharmacology
  • Phenylcarbamates / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction* / drug effects
  • Stress, Physiological* / drug effects
  • Transcription Factor CHOP / metabolism
  • Transfection
  • Tunicamycin / pharmacology
  • beta-N-Acetylhexosaminidases / antagonists & inhibitors
  • beta-N-Acetylhexosaminidases / genetics
  • beta-N-Acetylhexosaminidases / metabolism

Substances

  • Ddit3 protein, rat
  • Enzyme Inhibitors
  • Oximes
  • Phenylcarbamates
  • Tunicamycin
  • N-acetylglucosaminono-1,5-lactone O-(phenylcarbamoyl)oxime
  • Transcription Factor CHOP
  • Brefeldin A
  • N-Acetylglucosaminyltransferases
  • O-GlcNAc transferase
  • hexosaminidase C
  • beta-N-Acetylhexosaminidases
  • Acetylglucosamine