Adenovirus-mediated overexpression of O-GlcNAcase improves contractile function in the diabetic heart.
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.
Hu
Ying
Y
Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, Calif 92093-0618, USA.
Belke
Darrell
D
Suarez
Jorge
J
Swanson
Eric
E
Clark
Raymond
R
Hoshijima
Masahiko
M
Dillmann
Wolfgang H
WH
D000118:Acetylglucosaminidase / Q000235:genetics / Q000378:metabolism*; D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D005822:Genetic Vectors; D051548:Histone Acetyltransferases; D051379:Mice; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D001619:beta-N-Acetylhexosaminidases
D009097:Multienzyme Complexes; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; C110628:hexosaminidase C; D000118:Acetylglucosaminidase; D001619:beta-N-Acetylhexosaminidases; D002118:Calcium