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

Abstract

Objectives: 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 MT cardiac protection against diabetes is mediated by inactivation of glycogen synthase kinase-3β (GSK-3β).

Research Design and Methods: Diabetes was induced with streptozotocin in both MT-TG and wild-type (WT) 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 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 WT diabetic mice, but not MT-TG diabetic mice. Correspondingly, cardiac glycogen synthase (GS) phosphorylation, hexokinase II (HK II), PPAR α and PGC-1α expression, which mediate glucose and lipid metabolisms, were significantly changed along with cardiac lipid accumulation, inflammation (TNF-α, PAI-1 and ICAM-1), nitrosative damage (3-nitrotyrosin accumulation), and fibrosis in the WT diabetic mice. The above pathological changes were completely prevented either by cardiac MT in the MT-TG diabetic mice or by inhibition of GSK-3β activity in the WT diabetic mice with 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. MT inactivation of GSK-3β plays a critical role in preventing diabetic cardiomyopathy.