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

Wang Y, Feng W, Xue W, Tan Y, Hein DW, Li XK, Cai L - Diabetes (2009)

Bottom Line: Glycogen synthase kinase (GSK)-3beta plays an important role in cardiomyopathies.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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Diabetes-increased cardiac nitrosative damage and fibrosis. Cardiac nitrosative damage was examined by 3-NT accumulation with Western blotting analysis (A). Cardiac fibrosis was examined by Western blotting analysis of CTGF expression (B) and Sirius Red staining of collagen (C). *P < 0.05 vs. corresponding controls. Ms, months; Ws, weeks; WT, wild type. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 6: Diabetes-increased cardiac nitrosative damage and fibrosis. Cardiac nitrosative damage was examined by 3-NT accumulation with Western blotting analysis (A). Cardiac fibrosis was examined by Western blotting analysis of CTGF expression (B) and Sirius Red staining of collagen (C). *P < 0.05 vs. corresponding controls. Ms, months; Ws, weeks; WT, wild type. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: Cardiac lipid accumulation and associated inflammation were accompanied by significant cardiac nitrosative damage, examined by Western blotting assay for 3-NT as an index of nitrosative damage in the wild-type diabetic mice—an effect not observed in the MT-TG diabetic mice (Fig. 6A). In addition, because the proinflammatory cytokine PAI-1 is also profibrotic given its inhibition of the conversion of plasminogen to plasmin, we next examined the diabetic effect on cardiac fibrosis. As shown in Fig. 6, diabetes increased cardiac CTGF expression (Fig. 6B) and collagen deposition (evidenced by Sirius Red staining) (Fig. 6C) in the wild-type, but not MT-TG, mice.


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

Wang Y, Feng W, Xue W, Tan Y, Hein DW, Li XK, Cai L - Diabetes (2009)

Diabetes-increased cardiac nitrosative damage and fibrosis. Cardiac nitrosative damage was examined by 3-NT accumulation with Western blotting analysis (A). Cardiac fibrosis was examined by Western blotting analysis of CTGF expression (B) and Sirius Red staining of collagen (C). *P < 0.05 vs. corresponding controls. Ms, months; Ws, weeks; WT, wild type. (A high-quality digital representation of this figure is available in the online issue.)
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2682666&req=5

Figure 6: Diabetes-increased cardiac nitrosative damage and fibrosis. Cardiac nitrosative damage was examined by 3-NT accumulation with Western blotting analysis (A). Cardiac fibrosis was examined by Western blotting analysis of CTGF expression (B) and Sirius Red staining of collagen (C). *P < 0.05 vs. corresponding controls. Ms, months; Ws, weeks; WT, wild type. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: Cardiac lipid accumulation and associated inflammation were accompanied by significant cardiac nitrosative damage, examined by Western blotting assay for 3-NT as an index of nitrosative damage in the wild-type diabetic mice—an effect not observed in the MT-TG diabetic mice (Fig. 6A). In addition, because the proinflammatory cytokine PAI-1 is also profibrotic given its inhibition of the conversion of plasminogen to plasmin, we next examined the diabetic effect on cardiac fibrosis. As shown in Fig. 6, diabetes increased cardiac CTGF expression (Fig. 6B) and collagen deposition (evidenced by Sirius Red staining) (Fig. 6C) in the wild-type, but not MT-TG, mice.

Bottom Line: Glycogen synthase kinase (GSK)-3beta plays an important role in cardiomyopathies.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

Show MeSH
Related in: MedlinePlus