This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 117/9/1172    most recent CIRCULATIONAHA.107.730515v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Google Scholar Articles by Jones, S. P. Articles by Marbán, E. PubMed PubMed Citation Articles by Jones, S. P. Articles by Marbán, E. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Cardiomyopathy Related Collections Biochemistry and metabolism Oxidant stress Animal models of human disease Apoptosis Related Article

(Circulation. 2008;117:1172-1182.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

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; 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.

Correspondence to Steven P. Jones, PhD, Institute of Molecular Cardiology, 580 S Preston St, Baxter II, 404C, Louisville, KY 40202. E-mail Steven.P.Jones{at}Louisville.edu

Received July 26, 2007; accepted December 14, 2007.

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.

---

 

CLINICAL PERSPECTIVE

Related Article:

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

This article has been cited by other articles:

				Q. Wang, R. V. Donthi, J. Wang, A. J. Lange, L. J. Watson, S. P. Jones, and P. N. Epstein Cardiac phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase increases glycolysis, hypertrophy, and myocyte resistance to hypoxia Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2889 - H2897. [Abstract] [Full Text] [PDF]