Affiliation:
1. From the Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, Calif.
Abstract
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 Ca
2+
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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine,Physiology
Cited by
195 articles.
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