Cardioprotection by N -Acetylglucosamine Linkage to Cellular Proteins

Abstract

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.