Cardioprotection by N-Acetylglucosamine Linkage to Cellular Proteins

SP Jones, NE Zachara, GA Ngoh, BG Hill, Y Teshima… - Circulation, 2008 - Am Heart Assoc
SP Jones, NE Zachara, GA Ngoh, BG Hill, Y Teshima, A Bhatnagar, GW Hart, E Marbán
Circulation, 2008Am Heart Assoc
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 …
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.
Am Heart Assoc