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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

Inhibition of GSK-3β by its inhibitor attenuated diabetes-induced changes related to glucose and lipid metabolism. Once diabetes was diagnosed on day 3 after mice were injected with STZ, half of these diabetic mice were immediately administered GSK-3β–specific inhibitor SB216763 at 600 μg/kg every other day for 2 months, and then cardiac glycogen synthase (GS) phosphorylation (A), HK II expression (B), PPARα expression (C), and PGC-1α expression (D) were examined by Western blotting. Cardiac lipid accumulation was examined by Oil Red O staining (400×) (E). *P < 0.05 vs. corresponding controls; #P < 0.05 vs. corresponding diabetes. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 7: Inhibition of GSK-3β by its inhibitor attenuated diabetes-induced changes related to glucose and lipid metabolism. Once diabetes was diagnosed on day 3 after mice were injected with STZ, half of these diabetic mice were immediately administered GSK-3β–specific inhibitor SB216763 at 600 μg/kg every other day for 2 months, and then cardiac glycogen synthase (GS) phosphorylation (A), HK II expression (B), PPARα expression (C), and PGC-1α expression (D) were examined by Western blotting. Cardiac lipid accumulation was examined by Oil Red O staining (400×) (E). *P < 0.05 vs. corresponding controls; #P < 0.05 vs. corresponding diabetes. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: The above results indicate that inactivation of GSK-3β by metallothionein in the MT-TG diabetic mice seems to lead to the prevention of diabetes-induced cardiac energy metabolism derangement, lipid accumulation, inflammation, oxidative damage, and remodeling. To define whether the activation of GSK-3β by its dephosphorylation is directly related to diabetes-induced pathogenic effects, GSK-3β–specific inhibitor SB216763 was given to the wild-type diabetic mice at 600 μg/kg body wt every other day for 2 months immediately after the onset of diabetes. Inhibition of GSK-3β activity completely prevented diabetes-induced glycogen synthase phosphorylation (Fig. 7A), HK II downregulation (Fig. 7B), PPARα upregulation (Fig. 7C), PGC-1 downregulation (Fig. 7D), and lipid accumulation (Fig. 7E) in the heart of the wild-type 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)

Inhibition of GSK-3β by its inhibitor attenuated diabetes-induced changes related to glucose and lipid metabolism. Once diabetes was diagnosed on day 3 after mice were injected with STZ, half of these diabetic mice were immediately administered GSK-3β–specific inhibitor SB216763 at 600 μg/kg every other day for 2 months, and then cardiac glycogen synthase (GS) phosphorylation (A), HK II expression (B), PPARα expression (C), and PGC-1α expression (D) were examined by Western blotting. Cardiac lipid accumulation was examined by Oil Red O staining (400×) (E). *P < 0.05 vs. corresponding controls; #P < 0.05 vs. corresponding diabetes. (A high-quality digital representation of this figure is available in the online issue.)
© Copyright Policy
Related In: Results  -  Collection

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

Figure 7: Inhibition of GSK-3β by its inhibitor attenuated diabetes-induced changes related to glucose and lipid metabolism. Once diabetes was diagnosed on day 3 after mice were injected with STZ, half of these diabetic mice were immediately administered GSK-3β–specific inhibitor SB216763 at 600 μg/kg every other day for 2 months, and then cardiac glycogen synthase (GS) phosphorylation (A), HK II expression (B), PPARα expression (C), and PGC-1α expression (D) were examined by Western blotting. Cardiac lipid accumulation was examined by Oil Red O staining (400×) (E). *P < 0.05 vs. corresponding controls; #P < 0.05 vs. corresponding diabetes. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: The above results indicate that inactivation of GSK-3β by metallothionein in the MT-TG diabetic mice seems to lead to the prevention of diabetes-induced cardiac energy metabolism derangement, lipid accumulation, inflammation, oxidative damage, and remodeling. To define whether the activation of GSK-3β by its dephosphorylation is directly related to diabetes-induced pathogenic effects, GSK-3β–specific inhibitor SB216763 was given to the wild-type diabetic mice at 600 μg/kg body wt every other day for 2 months immediately after the onset of diabetes. Inhibition of GSK-3β activity completely prevented diabetes-induced glycogen synthase phosphorylation (Fig. 7A), HK II downregulation (Fig. 7B), PPARα upregulation (Fig. 7C), PGC-1 downregulation (Fig. 7D), and lipid accumulation (Fig. 7E) in the heart of the wild-type 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