title: Cardioprotection by N-acetylglucosamine linkage to cellular proteins.
abstract: BACKGROUND
  The modification of proteins with O-linked beta-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.
  
  
  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.
authors.affiliation: Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY 40202, USA. Steven.P.Jones@Louisville.edu
authors.forename: Steven P
authors.initials: SP
authors.lastname: Jones
authors.forename: Natasha E
authors.initials: NE
authors.lastname: Zachara
authors.forename: Gladys A
authors.initials: GA
authors.lastname: Ngoh
authors.forename: Bradford G
authors.initials: BG
authors.lastname: Hill
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Teshima
authors.forename: Aruni
authors.initials: A
authors.lastname: Bhatnagar
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Hart
authors.forename: Eduardo
authors.initials: E
authors.lastname: Marbán
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D002316:Cardiotonic Agents / Q000378:metabolism*; D002478:Cells, Cultured; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology
chemical_list: D002316:Cardiotonic Agents; D008565:Membrane Proteins; D000117:Acetylglucosamine