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Circulation. 2008 Mar 4;117(9):1172-82. doi: 10.1161/CIRCULATIONAHA.107.730515. Epub 2008 Feb 19.

Cardioprotection by N-acetylglucosamine linkage to cellular proteins.

Author information

1
Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY 40202, USA. Steven.P.Jones@Louisville.edu

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.

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.

[Indexed for MEDLINE]

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