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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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Diabetic (DM) rats showed excessive myocardial lipids deposition and inflammation. A: Representative Oil Red O–stained myocardial sections (scale bar: 20 μm). B: Semiquantification of Oil Red O staining. Data are mean ± SEM of six independent observations in each group. C and D: Relative mRNA expression of myocardial TNF-α and IL-6. E: Immunohistochemical staining for myocardial TNF-α and IL-6 (brown staining considered positive staining; scale bar: 50 μm). F: Representative Western blot of myocardial TNF-α and IL-6. G and H: Western blot analyses of TNF-α (G) and IL-6 (H). Data are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control; ††P < 0.01, ‡P < 0.001 vs. HF; #P < 0.05, ##P < 0.01 vs. chow + STZ. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 4: Diabetic (DM) rats showed excessive myocardial lipids deposition and inflammation. A: Representative Oil Red O–stained myocardial sections (scale bar: 20 μm). B: Semiquantification of Oil Red O staining. Data are mean ± SEM of six independent observations in each group. C and D: Relative mRNA expression of myocardial TNF-α and IL-6. E: Immunohistochemical staining for myocardial TNF-α and IL-6 (brown staining considered positive staining; scale bar: 50 μm). F: Representative Western blot of myocardial TNF-α and IL-6. G and H: Western blot analyses of TNF-α (G) and IL-6 (H). Data are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control; ††P < 0.01, ‡P < 0.001 vs. HF; #P < 0.05, ##P < 0.01 vs. chow + STZ. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: Coincident with cardiac dysfunction and hypertrophy, myocardial lipid analysis revealed striking myocardial accumulation of triglycerides in diabetic rats (Fig. 4A and B). Diabetic rats had higher Oil Red O–staining areas than other groups (Fig. 4B). The mRNA expression levels of TNF-α and IL-6 were significantly higher in the diabetic group compared with the control (P < 0.05, P < 0.01) (Fig. 4C and D). The protein expression levels of TNF-α and IL-6 were significantly increased in the diabetic group compared with the other three groups (Fig. 4E–H). Likewise, the protein expression of TNF-α and IL-6 content was increased in the chow + STZ and HF groups compared with the control (P < 0.01 ∼ P < 0.001) (Fig. 4F–H).


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)

Diabetic (DM) rats showed excessive myocardial lipids deposition and inflammation. A: Representative Oil Red O–stained myocardial sections (scale bar: 20 μm). B: Semiquantification of Oil Red O staining. Data are mean ± SEM of six independent observations in each group. C and D: Relative mRNA expression of myocardial TNF-α and IL-6. E: Immunohistochemical staining for myocardial TNF-α and IL-6 (brown staining considered positive staining; scale bar: 50 μm). F: Representative Western blot of myocardial TNF-α and IL-6. G and H: Western blot analyses of TNF-α (G) and IL-6 (H). Data are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control; ††P < 0.01, ‡P < 0.001 vs. HF; #P < 0.05, ##P < 0.01 vs. chow + STZ. (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 4: Diabetic (DM) rats showed excessive myocardial lipids deposition and inflammation. A: Representative Oil Red O–stained myocardial sections (scale bar: 20 μm). B: Semiquantification of Oil Red O staining. Data are mean ± SEM of six independent observations in each group. C and D: Relative mRNA expression of myocardial TNF-α and IL-6. E: Immunohistochemical staining for myocardial TNF-α and IL-6 (brown staining considered positive staining; scale bar: 50 μm). F: Representative Western blot of myocardial TNF-α and IL-6. G and H: Western blot analyses of TNF-α (G) and IL-6 (H). Data are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control; ††P < 0.01, ‡P < 0.001 vs. HF; #P < 0.05, ##P < 0.01 vs. chow + STZ. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: Coincident with cardiac dysfunction and hypertrophy, myocardial lipid analysis revealed striking myocardial accumulation of triglycerides in diabetic rats (Fig. 4A and B). Diabetic rats had higher Oil Red O–staining areas than other groups (Fig. 4B). The mRNA expression levels of TNF-α and IL-6 were significantly higher in the diabetic group compared with the control (P < 0.05, P < 0.01) (Fig. 4C and D). The protein expression levels of TNF-α and IL-6 were significantly increased in the diabetic group compared with the other three groups (Fig. 4E–H). Likewise, the protein expression of TNF-α and IL-6 content was increased in the chow + STZ and HF groups compared with the control (P < 0.01 ∼ P < 0.001) (Fig. 4F–H).

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