Published Online
on February 19, 2008

A more recent version of this article appeared on March 4, 2008

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Submitted on July 26, 2007
Accepted on December 14, 2007

Cardioprotection by N-Acetylglucosamine Linkage to Cellular Proteins

Steven P. Jones PhD^*, Natasha E. Zachara PhD, Gladys A. Ngoh MS, Bradford G. Hill PhD, Yasushi Teshima MD, PhD, Aruni Bhatnagar PhD, Gerald W. Hart PhD, and Eduardo Marbán MD, PhD

From the Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, Ky (S.P.J., G.A.N., B.G.H., A.B.); and Department of Biological Chemistry (N.E.Z., G.W.H.), Institute of Molecular Cardiobiology (Y.T., E.M.), and Johns Hopkins University National Heart, Lung, and Blood Institute Proteomics Center (G.W.H., E.M.), Johns Hopkins University School of Medicine, Baltimore, Md.

^* To whom correspondence should be addressed. E-mail: Steven.P.Jones{at}Louisville.edu.

Background—The modification of proteins with O-linked -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.

Key words: infarction • ischemia • mitochondria • myocardial infarction • acetylglucosamine

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Circulation 2008 117: 1121-1123. [Extract] [Full Text]

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