title: Inactivation of GSK-3beta by metallothionein prevents diabetes-related changes in cardiac energy metabolism, inflammation, nitrosative damage, and remodeling.
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.
  
  
  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.
authors.affiliation: Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical College, Zhejiang, China.
authors.forename: Yuehui
authors.initials: Y
authors.lastname: Wang
authors.forename: Wenke
authors.initials: W
authors.lastname: Feng
authors.forename: Wanli
authors.initials: W
authors.lastname: Xue
authors.forename: Yi
authors.initials: Y
authors.lastname: Tan
authors.forename: David W
authors.initials: DW
authors.lastname: Hein
authors.forename: Xiao-Kun
authors.initials: XK
authors.lastname: Li
authors.forename: Lu
authors.initials: L
authors.lastname: Cai