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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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Related in: MedlinePlus

Pathology features of DCM. Cardiac hypertrophy in diabetic (DM) rats. A1: Heart size (scale bar: 2 mm). A2: Representative cross sections of hearts at the papillary muscle level (scale bar: 2 mm). A3: Longitudinal sections of LV stained with hematoxylin and eosin (H&E; scale bar: 50 μm). A4: Transverse sections of LV stained with H&E (scale bar: 50 μm). B: Quantitative data of heart weight to body weight (HW-to-BW) ratio. C: Morphometric quantification of myocyte size. D: Relative mRNA expression of brain natriuretic protein (BNP). E: Cardiac fibrosis in diabetic rats is shown. Masson trichrome staining (collagen is green and myocardium red; scale bar: 50 μm [E1]) and Picrosirius red staining (collagen fibers stained bright red, bright-field [E2], dark-field [E3]; scale bar: 100 μm) show interstitial fibrosis. Masson trichrome staining (E4) (scale bar: 100 μm) and Picrosirius red staining (bright-field [E5], dark-field [E6]; scale bar: 100 μm) show perivascular fibrosis. F: Quantitative analysis of CVF. G: Collagen content determined by hydroxyproline assay. H: Quantitative analysis of PVCA/LA. Data are mean ± SEM; n = 6. *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 vs. chow + STZ. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 3: Pathology features of DCM. Cardiac hypertrophy in diabetic (DM) rats. A1: Heart size (scale bar: 2 mm). A2: Representative cross sections of hearts at the papillary muscle level (scale bar: 2 mm). A3: Longitudinal sections of LV stained with hematoxylin and eosin (H&E; scale bar: 50 μm). A4: Transverse sections of LV stained with H&E (scale bar: 50 μm). B: Quantitative data of heart weight to body weight (HW-to-BW) ratio. C: Morphometric quantification of myocyte size. D: Relative mRNA expression of brain natriuretic protein (BNP). E: Cardiac fibrosis in diabetic rats is shown. Masson trichrome staining (collagen is green and myocardium red; scale bar: 50 μm [E1]) and Picrosirius red staining (collagen fibers stained bright red, bright-field [E2], dark-field [E3]; scale bar: 100 μm) show interstitial fibrosis. Masson trichrome staining (E4) (scale bar: 100 μm) and Picrosirius red staining (bright-field [E5], dark-field [E6]; scale bar: 100 μm) show perivascular fibrosis. F: Quantitative analysis of CVF. G: Collagen content determined by hydroxyproline assay. H: Quantitative analysis of PVCA/LA. Data are mean ± SEM; n = 6. *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 vs. chow + STZ. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: The heart weight to body weight ratio was 25% higher in the diabetic group than the control group (P < 0.01) (Fig. 3B), and LV myocyte size was 40 and 31% higher, respectively, than the control and HF groups (P < 0.001) (Fig. 3C). Furthermore, the relative mRNA expression of brain natriuretic protein, a marker of LV hypertrophy (27), was higher in diabetic than control and HF rats (P < 0.05) (Fig. 3D).


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)

Pathology features of DCM. Cardiac hypertrophy in diabetic (DM) rats. A1: Heart size (scale bar: 2 mm). A2: Representative cross sections of hearts at the papillary muscle level (scale bar: 2 mm). A3: Longitudinal sections of LV stained with hematoxylin and eosin (H&E; scale bar: 50 μm). A4: Transverse sections of LV stained with H&E (scale bar: 50 μm). B: Quantitative data of heart weight to body weight (HW-to-BW) ratio. C: Morphometric quantification of myocyte size. D: Relative mRNA expression of brain natriuretic protein (BNP). E: Cardiac fibrosis in diabetic rats is shown. Masson trichrome staining (collagen is green and myocardium red; scale bar: 50 μm [E1]) and Picrosirius red staining (collagen fibers stained bright red, bright-field [E2], dark-field [E3]; scale bar: 100 μm) show interstitial fibrosis. Masson trichrome staining (E4) (scale bar: 100 μm) and Picrosirius red staining (bright-field [E5], dark-field [E6]; scale bar: 100 μm) show perivascular fibrosis. F: Quantitative analysis of CVF. G: Collagen content determined by hydroxyproline assay. H: Quantitative analysis of PVCA/LA. Data are mean ± SEM; n = 6. *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 vs. chow + STZ. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 3: Pathology features of DCM. Cardiac hypertrophy in diabetic (DM) rats. A1: Heart size (scale bar: 2 mm). A2: Representative cross sections of hearts at the papillary muscle level (scale bar: 2 mm). A3: Longitudinal sections of LV stained with hematoxylin and eosin (H&E; scale bar: 50 μm). A4: Transverse sections of LV stained with H&E (scale bar: 50 μm). B: Quantitative data of heart weight to body weight (HW-to-BW) ratio. C: Morphometric quantification of myocyte size. D: Relative mRNA expression of brain natriuretic protein (BNP). E: Cardiac fibrosis in diabetic rats is shown. Masson trichrome staining (collagen is green and myocardium red; scale bar: 50 μm [E1]) and Picrosirius red staining (collagen fibers stained bright red, bright-field [E2], dark-field [E3]; scale bar: 100 μm) show interstitial fibrosis. Masson trichrome staining (E4) (scale bar: 100 μm) and Picrosirius red staining (bright-field [E5], dark-field [E6]; scale bar: 100 μm) show perivascular fibrosis. F: Quantitative analysis of CVF. G: Collagen content determined by hydroxyproline assay. H: Quantitative analysis of PVCA/LA. Data are mean ± SEM; n = 6. *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 vs. chow + STZ. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: The heart weight to body weight ratio was 25% higher in the diabetic group than the control group (P < 0.01) (Fig. 3B), and LV myocyte size was 40 and 31% higher, respectively, than the control and HF groups (P < 0.001) (Fig. 3C). Furthermore, the relative mRNA expression of brain natriuretic protein, a marker of LV hypertrophy (27), was higher in diabetic than control and HF rats (P < 0.05) (Fig. 3D).

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