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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 glycogen synthase (GS) phosphorylation and decrease of HK II expression. Cardiac tissues were collected, as indicated in Fig. 1, for detecting total and phosphorylated glycogen synthase (Ser641) (A) and HK II expression (B) by Western blotting. *P < 0.05 vs. control. Ms, months; Ws, weeks; WT, wild type.
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Figure 2: Diabetes-induced glycogen synthase (GS) phosphorylation and decrease of HK II expression. Cardiac tissues were collected, as indicated in Fig. 1, for detecting total and phosphorylated glycogen synthase (Ser641) (A) and HK II expression (B) by Western blotting. *P < 0.05 vs. control. Ms, months; Ws, weeks; WT, wild type.

Mentions: Two major functions of GSK-3β are its negative regulation of glucose metabolism and positive involvement in apoptotic cell death pathway (9). We have demonstrated the protection of metallothionein against diabetes-induced cardiac cell death (22). In the following experiments, therefore, we focus on effects of GSK-3β on energy metabolism–related molecules and associated pathogenic damages. Significantly increased glycogen synthase phosphorylation was observed in the hearts of wild-type diabetic mice 2 and 5 months, but not 2 weeks, after diabetes onset (Fig. 2A). Diabetes also significantly decreased HK II protein levels in the hearts of wild-type mice from 2 weeks until 5 months (Fig. 2B). However, both altered glycogen synthase phosphorylation and HK II abundance were normalized in the MT-TG diabetic hearts (Fig. 2), suggesting that glycogen synthesis and glucose metabolism decreased in the hearts of wild-type diabetic mice but not 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 glycogen synthase (GS) phosphorylation and decrease of HK II expression. Cardiac tissues were collected, as indicated in Fig. 1, for detecting total and phosphorylated glycogen synthase (Ser641) (A) and HK II expression (B) by Western blotting. *P < 0.05 vs. control. Ms, months; Ws, weeks; WT, wild type.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Diabetes-induced glycogen synthase (GS) phosphorylation and decrease of HK II expression. Cardiac tissues were collected, as indicated in Fig. 1, for detecting total and phosphorylated glycogen synthase (Ser641) (A) and HK II expression (B) by Western blotting. *P < 0.05 vs. control. Ms, months; Ws, weeks; WT, wild type.
Mentions: Two major functions of GSK-3β are its negative regulation of glucose metabolism and positive involvement in apoptotic cell death pathway (9). We have demonstrated the protection of metallothionein against diabetes-induced cardiac cell death (22). In the following experiments, therefore, we focus on effects of GSK-3β on energy metabolism–related molecules and associated pathogenic damages. Significantly increased glycogen synthase phosphorylation was observed in the hearts of wild-type diabetic mice 2 and 5 months, but not 2 weeks, after diabetes onset (Fig. 2A). Diabetes also significantly decreased HK II protein levels in the hearts of wild-type mice from 2 weeks until 5 months (Fig. 2B). However, both altered glycogen synthase phosphorylation and HK II abundance were normalized in the MT-TG diabetic hearts (Fig. 2), suggesting that glycogen synthesis and glucose metabolism decreased in the hearts of wild-type diabetic mice but not 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