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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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Related in: MedlinePlus

Diabetes-induced cardiac inflammation. Real-time RT-PCR was used to examine the expression of TNF-α (A), ICAM-1 (B), and PAI-1 mRNA (C) in the hearts of diabetic mice at indicated postdiabetic times. TNF-α, ICAM-1, and PAI-1 expressions were normalized to GAPDH, by which the fold changes in expression were calculated using 2−ΔΔCt method. Expression of PAI-1 was further confirmed for its protein level by Western blotting (D) and localization by immunohistochemical staining (E). *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 4: Diabetes-induced cardiac inflammation. Real-time RT-PCR was used to examine the expression of TNF-α (A), ICAM-1 (B), and PAI-1 mRNA (C) in the hearts of diabetic mice at indicated postdiabetic times. TNF-α, ICAM-1, and PAI-1 expressions were normalized to GAPDH, by which the fold changes in expression were calculated using 2−ΔΔCt method. Expression of PAI-1 was further confirmed for its protein level by Western blotting (D) and localization by immunohistochemical staining (E). *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: We next determined whether altered glucose and lipid metabolisms are accompanied by cardiac inflammation by detecting a few inflammatory cytokines that were found to play critical roles in the pathogenesis of diabetic cardiomyopathy (23,24). Real-time RT-PCR analysis showed that TNF-α and ICAM-1 mRNA expression in the hearts of wild-type diabetic mice was significantly increased 2 weeks and 5 months (Fig. 4A) and 2 weeks and 2 months (Fig. 4B) after diabetes, respectively. PAI-1 mRNA expression was significantly increased in the hearts of wild-type diabetic mice from 2 weeks to 5 months after diabetes (Fig. 4C). In addition, the increased PAI-1 expression in the hearts of wild-type diabetic mice was further confirmed by Western blot analysis (Fig. 4D) and immunohistochemical localization (Fig. 4E). However, the induction of inflammatory cytokine expression was not observed in the hearts of MT-TG diabetic 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-induced cardiac inflammation. Real-time RT-PCR was used to examine the expression of TNF-α (A), ICAM-1 (B), and PAI-1 mRNA (C) in the hearts of diabetic mice at indicated postdiabetic times. TNF-α, ICAM-1, and PAI-1 expressions were normalized to GAPDH, by which the fold changes in expression were calculated using 2−ΔΔCt method. Expression of PAI-1 was further confirmed for its protein level by Western blotting (D) and localization by immunohistochemical staining (E). *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

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getmorefigures.php?uid=PMC2682666&req=5

Figure 4: Diabetes-induced cardiac inflammation. Real-time RT-PCR was used to examine the expression of TNF-α (A), ICAM-1 (B), and PAI-1 mRNA (C) in the hearts of diabetic mice at indicated postdiabetic times. TNF-α, ICAM-1, and PAI-1 expressions were normalized to GAPDH, by which the fold changes in expression were calculated using 2−ΔΔCt method. Expression of PAI-1 was further confirmed for its protein level by Western blotting (D) and localization by immunohistochemical staining (E). *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: We next determined whether altered glucose and lipid metabolisms are accompanied by cardiac inflammation by detecting a few inflammatory cytokines that were found to play critical roles in the pathogenesis of diabetic cardiomyopathy (23,24). Real-time RT-PCR analysis showed that TNF-α and ICAM-1 mRNA expression in the hearts of wild-type diabetic mice was significantly increased 2 weeks and 5 months (Fig. 4A) and 2 weeks and 2 months (Fig. 4B) after diabetes, respectively. PAI-1 mRNA expression was significantly increased in the hearts of wild-type diabetic mice from 2 weeks to 5 months after diabetes (Fig. 4C). In addition, the increased PAI-1 expression in the hearts of wild-type diabetic mice was further confirmed by Western blot analysis (Fig. 4D) and immunohistochemical localization (Fig. 4E). However, the induction of inflammatory cytokine expression was not observed in the hearts of MT-TG diabetic 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