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Diabetes. 2009 Jun;58(6):1391-402. doi: 10.2337/db08-1697. Epub 2009 Mar 26.

Inactivation of GSK-3beta by metallothionein prevents diabetes-related changes in cardiac energy metabolism, inflammation, nitrosative damage, and remodeling.

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1
Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical College, Zhejiang, China.

Abstract

OBJECTIVE:

Glycogen synthase kinase (GSK)-3beta plays an important role in cardiomyopathies. Cardiac-specific metallothionein-overexpressing transgenic (MT-TG) mice were highly resistant to diabetes-induced cardiomyopathy. Therefore, we investigated whether metallothionein cardiac protection against diabetes is mediated by inactivation of GSK-3beta.

RESEARCH DESIGN AND METHODS:

Diabetes was induced with streptozotocin in both MT-TG and wild-type mice. Changes of energy metabolism-related molecules, lipid accumulation, inflammation, nitrosative damage, and fibrotic remodeling were examined in the hearts of diabetic mice 2 weeks, 2 months, and 5 months after the onset of diabetes with Western blotting, RT-PCR, and immunohistochemical assays.

RESULTS:

Activation (dephosphorylation) of GSK-3beta was evidenced in the hearts of wild-type diabetic mice but not MT-TG diabetic mice. Correspondingly, cardiac glycogen synthase phosphorylation, hexokinase II, PPARalpha, and PGC-1alpha expression, which mediate glucose and lipid metabolisms, were significantly changed along with cardiac lipid accumulation, inflammation (TNF-alpha, plasminogen activator inhibitor 1 [PAI-1], and intracellular adhesion molecule 1 [ICAM-1]), nitrosative damage (3-nitrotyrosin accumulation), and fibrosis in the wild-type diabetic mice. The above pathological changes were completely prevented either by cardiac metallothionein in the MT-TG diabetic mice or by inhibition of GSK-3beta activity in the wild-type diabetic mice with a GSK-3beta-specific inhibitor.

CONCLUSIONS:

These results suggest that activation of GSK-3beta plays a critical role in diabetes-related changes in cardiac energy metabolism, inflammation, nitrosative damage, and remodeling. Metallothionein inactivation of GSK-3beta plays a critical role in preventing diabetic cardiomyopathy.

PMID:
19324938
PMCID:
PMC2682666
DOI:
10.2337/db08-1697
[Indexed for MEDLINE]
Free PMC Article
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