Cardioprotection by N-acetylglucosamine linkage to cellular proteins.
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.
Jones
Steven P
SP
Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY 40202, USA. Steven.P.Jones@Louisville.edu
Zachara
Natasha E
NE
Ngoh
Gladys A
GA
Hill
Bradford G
BG
Teshima
Yasushi
Y
Bhatnagar
Aruni
A
Hart
Gerald W
GW
Marbán
Eduardo
E
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
D002316:Cardiotonic Agents; D008565:Membrane Proteins; D000117:Acetylglucosamine