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(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

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A Bittersweet Modification: O-GlcNAc and Cardiac Dysfunction

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