This Article Full Text Full Text (PDF) All Versions of this Article: 96/9/1006    most recent 01.RES.0000165478.06813.58v1 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 Citing Articles via Google Scholar Google Scholar Articles by Hu, Y. Articles by Dillmann, W. H. Search for Related Content PubMed PubMed Citation Articles by Hu, Y. Articles by Dillmann, W. H. Related Collections Contractile function Gene therapy Type 1 diabetes Animal models of human disease Calcium cycling/excitation-contraction coupling Related Article

(Circulation Research. 2005;96:1006.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Adenovirus-Mediated Overexpression of O-GlcNAcase Improves Contractile Function in the Diabetic Heart

Ying Hu, Darrell Belke, Jorge Suarez, Eric Swanson, Raymond Clark, Masahiko Hoshijima, Wolfgang H. Dillmann

From the Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, Calif.

Correspondence to Wolfgang H. Dillmann, Department of Medicine, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0618. E-mail wdillman{at}ucsd.edu

To examine whether excessive protein O-GlcNAcylation plays a role in the dysfunction of the diabetic heart, we delivered adenovirus expressing O-GlcNAcase (Adv-GCA) into the myocardium of STZ-induced diabetic mice. Our results indicated that excessive cellular O-GlcNAcylation exists in the diabetic heart, and that in vivo GCA overexpression reduces overall cellular O-GlcNAcylation. Myocytes isolated from diabetic hearts receiving Adv-GCA exhibited improved calcium transients with a significantly shortened T_decay (P<0.01) and increased sarcoplasmic reticulum Ca²⁺ load (P<0.01). These myocytes also demonstrated improved contractility including a significant increase in +dL/dt and –dL/dt and greater fractional shortening as measured by edge detection (P<0.01). In isolated perfused hearts, developed pressure and –dP/dt were significantly improved in diabetic hearts receiving Adv-GCA (P<0.05). These hearts also exhibited a 40% increase in SERCA2a expression. Phospholamban protein expression was reduced 50%, but the phosphorylated form was increased 2-fold in the diabetic hearts receiving Adv-GCA. We conclude that excess O-GlcNAcylation in the diabetic heart contributes to cardiac dysfunction, and reducing this excess cellular O-GlcNAcylation has beneficial effects on calcium handling and diabetic cardiac function.

Key Words: O-GlcNAcase • adenovirus • gene therapy • diabetic cardiomyopathy • Ca²⁺ handling

Related Article:

A Bittersweet Modification: O-GlcNAc and Cardiac Dysfunction

Steven P. Jones
Circ. Res. 2005 96: 925-926. [Full Text] [PDF]

This article has been cited by other articles:

				R. J. Copeland, J. W. Bullen, and G. W. Hart Cross-talk between GlcNAcylation and phosphorylation: roles in insulin resistance and glucose toxicity Am J Physiol Endocrinol Metab, July 1, 2008; 295(1): E17 - E28. [Abstract] [Full Text] [PDF]

				B. Luo, Y. Soesanto, and D. A. McClain Protein Modification by O-Linked GlcNAc Reduces Angiogenesis by Inhibiting Akt Activity in Endothelial Cells Arterioscler. Thromb. Vasc. Biol., April 1, 2008; 28(4): 651 - 657. [Abstract] [Full Text] [PDF]

				J. Rengifo, C. J. Gibson, E. Winkler, T. Collin, and B. E. Ehrlich Regulation of the Inositol 1,4,5-Trisphosphate Receptor Type I by O-GlcNAc Glycosylation J. Neurosci., December 12, 2007; 27(50): 13813 - 13821. [Abstract] [Full Text] [PDF]

				J. Liu, R. B. Marchase, and J. C. Chatham Increased O-GlcNAc levels during reperfusion lead to improved functional recovery and reduced calpain proteolysis Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1391 - H1399. [Abstract] [Full Text] [PDF]

				N. E. Zachara The sweet nature of cardioprotection Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1324 - H1326. [Full Text] [PDF]

				N. Fulop, M. M. Mason, K. Dutta, P. Wang, A. J. Davidoff, R. B. Marchase, and J. C. Chatham Impact of Type 2 diabetes and aging on cardiomyocyte function and O-linked N-acetylglucosamine levels in the heart Am J Physiol Cell Physiol, April 1, 2007; 292(4): C1370 - C1378. [Abstract] [Full Text] [PDF]

				D. D. Belke, E. Swanson, J. Suarez, B. T. Scott, A. E. Stenbit, and W. H. Dillmann Increased expression of SERCA in the hearts of transgenic mice results in increased oxidation of glucose Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1755 - H1763. [Abstract] [Full Text] [PDF]

				K. A. Robinson, L. E. Ball, and M. G. Buse Reduction of O-GlcNAc protein modification does not prevent insulin resistance in 3T3-L1 adipocytes Am J Physiol Endocrinol Metab, March 1, 2007; 292(3): E884 - E890. [Abstract] [Full Text] [PDF]

				N. Fulop, R. B. Marchase, and J. C. Chatham Role of protein O-linked N-acetyl-glucosamine in mediating cell function and survival in the cardiovascular system Cardiovasc Res, January 15, 2007; 73(2): 288 - 297. [Abstract] [Full Text] [PDF]

				A. Martin and A. M. Planas Response to Letter by Tsuda Stroke, September 1, 2006; 37(9): 2200 - 2200. [Full Text] [PDF]

				J. G Leichman, D. Aguilar, T. M King, A. Vlada, M. Reyes, and H. Taegtmeyer Association of plasma free fatty acids and left ventricular diastolic function in patients with clinically severe obesity. Am. J. Clinical Nutrition, August 1, 2006; 84(2): 336 - 341. [Abstract] [Full Text] [PDF]

				L. E. Ball, M. N. Berkaw, and M. G. Buse Identification of the Major Site of O-Linked {beta}-N-Acetylglucosamine Modification in the C Terminus of Insulin Receptor Substrate-1 Mol. Cell. Proteomics, February 1, 2006; 5(2): 313 - 323. [Abstract] [Full Text] [PDF]

				S. P. Jones A Bittersweet Modification: O-GlcNAc and Cardiac Dysfunction Circ. Res., May 13, 2005; 96(9): 925 - 926. [Full Text] [PDF]