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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-increased PPARα expression and lipid accumulation. Cardiac tissues were collected, as indicated in Fig. 1, for detecting PPARα (A) and PGC-1α (B) expressions by Western blotting and cardiac lipid accumulation by Oil Red O staining (400×) (C) and triglyceride measurement (D). Panel D presents the data only from diabetic mice 2 weeks (Ws) after diabetes. *P < 0.05 vs. control; #P < 0.05 vs. wild-type (WT) diabetic group. Ms, months. (A high-quality digital representation of this figure is available in the online issue.).
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Figure 3: Diabetes-increased PPARα expression and lipid accumulation. Cardiac tissues were collected, as indicated in Fig. 1, for detecting PPARα (A) and PGC-1α (B) expressions by Western blotting and cardiac lipid accumulation by Oil Red O staining (400×) (C) and triglyceride measurement (D). Panel D presents the data only from diabetic mice 2 weeks (Ws) after diabetes. *P < 0.05 vs. control; #P < 0.05 vs. wild-type (WT) diabetic group. Ms, months. (A high-quality digital representation of this figure is available in the online issue.).

Mentions: The decreased glucose metabolism in the wild-type diabetic hearts was accompanied by increased cardiac PPARα expression (Fig. 3A), a positive mediator for fatty acid uptake and utilization. Furthermore, PGC-1α that acts as an essential regulator for the maintenance of maximal and efficient cardiac mitochondrial fatty acid oxidation was significantly depressed in the wild-type diabetic hearts but not in the MT-TG diabetic hearts (Fig. 3B). The increased PPARα and decreased PGC-1α indicate the imbalance of fatty acid metabolism. Consistent with this notion, diabetes significantly increased lipid accumulation in the hearts of wild-type mice but not MT-TG mice from 2 weeks to 5 months after the onset of diabetes, which was evidenced by Oil Red O staining (Fig. 3C) and biochemical measurement of triglyceride levels (Fig. 3D).


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 PPARα expression and lipid accumulation. Cardiac tissues were collected, as indicated in Fig. 1, for detecting PPARα (A) and PGC-1α (B) expressions by Western blotting and cardiac lipid accumulation by Oil Red O staining (400×) (C) and triglyceride measurement (D). Panel D presents the data only from diabetic mice 2 weeks (Ws) after diabetes. *P < 0.05 vs. control; #P < 0.05 vs. wild-type (WT) diabetic group. Ms, months. (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 3: Diabetes-increased PPARα expression and lipid accumulation. Cardiac tissues were collected, as indicated in Fig. 1, for detecting PPARα (A) and PGC-1α (B) expressions by Western blotting and cardiac lipid accumulation by Oil Red O staining (400×) (C) and triglyceride measurement (D). Panel D presents the data only from diabetic mice 2 weeks (Ws) after diabetes. *P < 0.05 vs. control; #P < 0.05 vs. wild-type (WT) diabetic group. Ms, months. (A high-quality digital representation of this figure is available in the online issue.).
Mentions: The decreased glucose metabolism in the wild-type diabetic hearts was accompanied by increased cardiac PPARα expression (Fig. 3A), a positive mediator for fatty acid uptake and utilization. Furthermore, PGC-1α that acts as an essential regulator for the maintenance of maximal and efficient cardiac mitochondrial fatty acid oxidation was significantly depressed in the wild-type diabetic hearts but not in the MT-TG diabetic hearts (Fig. 3B). The increased PPARα and decreased PGC-1α indicate the imbalance of fatty acid metabolism. Consistent with this notion, diabetes significantly increased lipid accumulation in the hearts of wild-type mice but not MT-TG mice from 2 weeks to 5 months after the onset of diabetes, which was evidenced by Oil Red O staining (Fig. 3C) and biochemical measurement of triglyceride levels (Fig. 3D).

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