Cardioprotection by N-acetylglucosamine linkage to cellular proteins

Steven P. Jones, Natasha E. Zachara, Gladys A. Ngoh, Bradford G. Hill, Yasushi Teshima, Aruni Bhatnagar, Gerald W. Hart, Eduardo Marbán

Research output: Contribution to journalArticlepeer-review

168 Scopus citations


BACKGROUND - The modification of proteins with O-linked β-N-acetylglucosamine (O-GlcNAc) represents a key posttranslational modification that modulates cellular function. Previous data suggest that O-GlcNAc may act as an intracellular metabolic or stress sensor, linking glucose metabolism to cellular function. Considering this, we hypothesized that augmentation of O-GlcNAc levels represents an endogenously recruitable mechanism of cardioprotection. METHODS AND RESULTS - In mouse hearts subjected to in vivo ischemic preconditioning, O-GlcNAc levels were significantly elevated. Pharmacological augmentation of O-GlcNAc levels in vivo was sufficient to reduce myocardial infarct size. We investigated the influence of O-GlcNAc levels on cardiac injury at the cellular level. Lethal oxidant stress of cardiac myocytes produced a time-dependent loss of cellular O-GlcNAc levels. This pathological response was largely reversible by pharmacological augmentation of O-GlcNAc levels and was associated with improved cardiac myocyte survival. The diminution of O-GlcNAc levels occurred synchronously with the loss of mitochondrial membrane potential in isolated cardiac myocytes. Pharmacological enhancement of O-GlcNAc levels attenuated the loss of mitochondrial membrane potential. Proteomic analysis identified voltage-dependent anion channel as a potential target of O-GlcNAc modification. Mitochondria isolated from adult mouse hearts with elevated O-GlcNAc levels had more O-GlcNAc-modified voltage-dependent anion channel and were more resistant to calcium-induced swelling than cardiac mitochondria from vehicle mice. CONCLUSIONS - O-GlcNAc signaling represents a unique endogenously recruitable mechanism of cardioprotection that may involve direct modification of mitochondrial proteins critical for survival such as voltage-dependent anion channel.

Original languageEnglish (US)
Pages (from-to)1172-1182
Number of pages11
Issue number9
StatePublished - Mar 2008


  • Acetylglucosamine
  • Infarction
  • Ischemia
  • Mitochondria
  • Myocardial infarction

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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