PT - JOURNAL ARTICLE AU - Wang, Yuehui AU - Feng, Wenke AU - Xue, Wanli AU - Tan, Yi AU - Hein, David W. AU - Li, Xiao-Kun AU - Cai, Lu TI - Inactivation of GSK-3β by Metallothionein Prevents Diabetes-Related Changes in Cardiac Energy Metabolism, Inflammation, Nitrosative Damage, and Remodeling AID - 10.2337/db08-1697 DP - 2009 Jun 01 TA - Diabetes PG - 1391--1402 VI - 58 IP - 6 4099 - http://diabetes.diabetesjournals.org/content/58/6/1391.short 4100 - http://diabetes.diabetesjournals.org/content/58/6/1391.full SO - Diabetes2009 Jun 01; 58 AB - OBJECTIVE Glycogen synthase kinase (GSK)-3β 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-3β. 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-3β was evidenced in the hearts of wild-type diabetic mice but not MT-TG diabetic mice. Correspondingly, cardiac glycogen synthase phosphorylation, hexokinase II, PPARα, and PGC-1α expression, which mediate glucose and lipid metabolisms, were significantly changed along with cardiac lipid accumulation, inflammation (TNF-α, 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-3β activity in the wild-type diabetic mice with a GSK-3β–specific inhibitor. CONCLUSIONS These results suggest that activation of GSK-3β plays a critical role in diabetes-related changes in cardiac energy metabolism, inflammation, nitrosative damage, and remodeling. Metallothionein inactivation of GSK-3β plays a critical role in preventing diabetic cardiomyopathy.