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TRB3 gene silencing alleviates diabetic cardiomyopathy in a type 2 diabetic rat model.

Ti Y, Xie GL, Wang ZH, Bi XL, Ding WY, Wang J, Jiang GH, Bu PL, Zhang Y, Zhong M, Zhang W - Diabetes (2011)

Bottom Line: We found that the silencing of TRB3 ameliorated metabolic disturbance and insulin resistance; myocardial hypertrophy, lipids accumulation, inflammation, fibrosis, and elevated collagen I-to-III content ratio in DCM rats were significantly decreased.These anatomic findings were accompanied by significant improvements in cardiac function.Furthermore, with TRB3 gene silencing, the inhibited phosphorylation of Akt was restored and the increased phosphorylation of extracellular signal-regulated kinase 1/2 and Jun NH(2)-terminal kinase in DCM was significantly decreased.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Ji’nan, Shandong Province, China.

ABSTRACT

Objective: Tribbles 3 (TRB3) is associated with insulin resistance, an important trigger in the development of diabetic cardiomyopathy (DCM). We sought to determine whether TRB3 plays a major role in modulating DCM and the mechanisms involved.

Research design and methods: The type 2 diabetic rat model was induced by high-fat diet and low-dose streptozotocin. We evaluated the characteristics of type 2 DCM by serial echocardiography and metabolite tests, Western blot analysis for TRB3 expression, and histopathologic analyses of cardiomyocyte density, lipids accumulation, cardiac inflammation, and fibrosis area. We then used gene silencing to investigate the role of TRB3 in the pathophysiologic features of DCM.

Results: Rats with DCM showed severe insulin resistance, left ventricular dysfunction, aberrant lipids deposition, cardiac inflammation, fibrosis, and TRB3 overexpression. We found that the silencing of TRB3 ameliorated metabolic disturbance and insulin resistance; myocardial hypertrophy, lipids accumulation, inflammation, fibrosis, and elevated collagen I-to-III content ratio in DCM rats were significantly decreased. These anatomic findings were accompanied by significant improvements in cardiac function. Furthermore, with TRB3 gene silencing, the inhibited phosphorylation of Akt was restored and the increased phosphorylation of extracellular signal-regulated kinase 1/2 and Jun NH(2)-terminal kinase in DCM was significantly decreased.

Conclusions: TRB3 gene silencing may exert a protective effect on DCM by improving selective insulin resistance, implicating its potential role for treatment of human DCM.

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Diabetes increases collagen I (coll I) and collagen III (coll III) content, suppresses Akt phosphorylation, and partly activates TRB3/MAPK pathway. A: Representative immunohistochemical staining of collagen I and III (brown staining considered positive staining; scale bar: 50 μm). B: Representative Western blot of collagen I and III content. C: Western blot analysis of collagen I, collagen III, and collagen I-to-III ratio. D: Relative mRNA expression and protein content of myocardial TRB3. E: Western blot analysis of p-Akt/Akt, p-ERK/ERK, p-p38/p38, and p-JNK/JNK. Data are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control; †P < 0.05, ††P < 0.01, ‡P < 0.001 vs. HF; #P < 0.05, ##P < 0.01, ###P < 0.001 vs. chow + STZ. DM, diabetic rats. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 5: Diabetes increases collagen I (coll I) and collagen III (coll III) content, suppresses Akt phosphorylation, and partly activates TRB3/MAPK pathway. A: Representative immunohistochemical staining of collagen I and III (brown staining considered positive staining; scale bar: 50 μm). B: Representative Western blot of collagen I and III content. C: Western blot analysis of collagen I, collagen III, and collagen I-to-III ratio. D: Relative mRNA expression and protein content of myocardial TRB3. E: Western blot analysis of p-Akt/Akt, p-ERK/ERK, p-p38/p38, and p-JNK/JNK. Data are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control; †P < 0.05, ††P < 0.01, ‡P < 0.001 vs. HF; #P < 0.05, ##P < 0.01, ###P < 0.001 vs. chow + STZ. DM, diabetic rats. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: Immunohistochemistry and Western blot analysis revealed the protein expression of collagen I and III content increased in the diabetic group (Fig. 5A and B), and the collagen I-to-III ratio significantly elevated compared with the control group (216 ± 16% vs. 100 ± 6%, respectively; P < 0.001) (Fig. 5C). Likewise, the protein expression of collagen I and III content was increased in the chow + STZ and HF groups compared with the control (P < 0.01 ∼ P < 0.001) (Fig. 5A–C).


TRB3 gene silencing alleviates diabetic cardiomyopathy in a type 2 diabetic rat model.

Ti Y, Xie GL, Wang ZH, Bi XL, Ding WY, Wang J, Jiang GH, Bu PL, Zhang Y, Zhong M, Zhang W - Diabetes (2011)

Diabetes increases collagen I (coll I) and collagen III (coll III) content, suppresses Akt phosphorylation, and partly activates TRB3/MAPK pathway. A: Representative immunohistochemical staining of collagen I and III (brown staining considered positive staining; scale bar: 50 μm). B: Representative Western blot of collagen I and III content. C: Western blot analysis of collagen I, collagen III, and collagen I-to-III ratio. D: Relative mRNA expression and protein content of myocardial TRB3. E: Western blot analysis of p-Akt/Akt, p-ERK/ERK, p-p38/p38, and p-JNK/JNK. Data are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control; †P < 0.05, ††P < 0.01, ‡P < 0.001 vs. HF; #P < 0.05, ##P < 0.01, ###P < 0.001 vs. chow + STZ. DM, diabetic rats. (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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Figure 5: Diabetes increases collagen I (coll I) and collagen III (coll III) content, suppresses Akt phosphorylation, and partly activates TRB3/MAPK pathway. A: Representative immunohistochemical staining of collagen I and III (brown staining considered positive staining; scale bar: 50 μm). B: Representative Western blot of collagen I and III content. C: Western blot analysis of collagen I, collagen III, and collagen I-to-III ratio. D: Relative mRNA expression and protein content of myocardial TRB3. E: Western blot analysis of p-Akt/Akt, p-ERK/ERK, p-p38/p38, and p-JNK/JNK. Data are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control; †P < 0.05, ††P < 0.01, ‡P < 0.001 vs. HF; #P < 0.05, ##P < 0.01, ###P < 0.001 vs. chow + STZ. DM, diabetic rats. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: Immunohistochemistry and Western blot analysis revealed the protein expression of collagen I and III content increased in the diabetic group (Fig. 5A and B), and the collagen I-to-III ratio significantly elevated compared with the control group (216 ± 16% vs. 100 ± 6%, respectively; P < 0.001) (Fig. 5C). Likewise, the protein expression of collagen I and III content was increased in the chow + STZ and HF groups compared with the control (P < 0.01 ∼ P < 0.001) (Fig. 5A–C).

Bottom Line: We found that the silencing of TRB3 ameliorated metabolic disturbance and insulin resistance; myocardial hypertrophy, lipids accumulation, inflammation, fibrosis, and elevated collagen I-to-III content ratio in DCM rats were significantly decreased.These anatomic findings were accompanied by significant improvements in cardiac function.Furthermore, with TRB3 gene silencing, the inhibited phosphorylation of Akt was restored and the increased phosphorylation of extracellular signal-regulated kinase 1/2 and Jun NH(2)-terminal kinase in DCM was significantly decreased.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Ji’nan, Shandong Province, China.

ABSTRACT

Objective: Tribbles 3 (TRB3) is associated with insulin resistance, an important trigger in the development of diabetic cardiomyopathy (DCM). We sought to determine whether TRB3 plays a major role in modulating DCM and the mechanisms involved.

Research design and methods: The type 2 diabetic rat model was induced by high-fat diet and low-dose streptozotocin. We evaluated the characteristics of type 2 DCM by serial echocardiography and metabolite tests, Western blot analysis for TRB3 expression, and histopathologic analyses of cardiomyocyte density, lipids accumulation, cardiac inflammation, and fibrosis area. We then used gene silencing to investigate the role of TRB3 in the pathophysiologic features of DCM.

Results: Rats with DCM showed severe insulin resistance, left ventricular dysfunction, aberrant lipids deposition, cardiac inflammation, fibrosis, and TRB3 overexpression. We found that the silencing of TRB3 ameliorated metabolic disturbance and insulin resistance; myocardial hypertrophy, lipids accumulation, inflammation, fibrosis, and elevated collagen I-to-III content ratio in DCM rats were significantly decreased. These anatomic findings were accompanied by significant improvements in cardiac function. Furthermore, with TRB3 gene silencing, the inhibited phosphorylation of Akt was restored and the increased phosphorylation of extracellular signal-regulated kinase 1/2 and Jun NH(2)-terminal kinase in DCM was significantly decreased.

Conclusions: TRB3 gene silencing may exert a protective effect on DCM by improving selective insulin resistance, implicating its potential role for treatment of human DCM.

Show MeSH
Related in: MedlinePlus