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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

TRB3 gene therapy decreases myocardial hypertrophy and fibrosis in HF and diabetic (DM) groups. 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 section of LV stained with H&E (scale bar: 50 μm). B–D: Quantitative data for heart weight to body weight (HW-to-BW) ratio, myocyte size, and relative brain natriuretic protein (BNP) mRNA expression. E1–6: Representative Masson trichrome staining and Picrosirius red staining. F–H: Quantitative analyses of CVF, collagen content, and PVCA/LA. Data are mean ± SEM; n = 7–10 per group. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 7: TRB3 gene therapy decreases myocardial hypertrophy and fibrosis in HF and diabetic (DM) groups. 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 section of LV stained with H&E (scale bar: 50 μm). B–D: Quantitative data for heart weight to body weight (HW-to-BW) ratio, myocyte size, and relative brain natriuretic protein (BNP) mRNA expression. E1–6: Representative Masson trichrome staining and Picrosirius red staining. F–H: Quantitative analyses of CVF, collagen content, and PVCA/LA. Data are mean ± SEM; n = 7–10 per group. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: With TRB3-siRNA treatment, heart weight-to-body weight ratio and myocyte size were significantly decreased in the diabetic versus the vehicle group (heart weight-to-body weight ratio: 2.67 ± 0.13 vs. 3.49 ± 0.36 mg/g, P < 0.05; myocyte size: 384.32 ± 8.69 vs. 440.14 ± 4.47 μm2, P < 0.01) (Fig. 7B and C). The mRNA expression of brain natriuretic protein was lower in both the HF and diabetic groups than in the vehicle control (P < 0.001) (Fig. 7D). CVF and PVCA/LA were reduced (P < 0.001, P < 0.01) (Fig. 7F and H). In addition, collagen content was lower in the diabetic group than the vehicle group (10.17 ± 0.41 vs. 13.84 ± 0.48 μg/mg LV weight, respectively; P < 0.001) (Fig. 7G). Likewise, CVF and PVCA/LA were decreased in the TRB3-siRNA HF group (P < 0.05, P < 0.01) (Fig. 7F and H). In keeping with these observations, the decreased IB% and increased CVIB acquired from the IBS of the LV reconfirmed the improved pathological manifestations (P < 0.05 ∼ P < 0.001) (Supplementary Table 4).


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)

TRB3 gene therapy decreases myocardial hypertrophy and fibrosis in HF and diabetic (DM) groups. 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 section of LV stained with H&E (scale bar: 50 μm). B–D: Quantitative data for heart weight to body weight (HW-to-BW) ratio, myocyte size, and relative brain natriuretic protein (BNP) mRNA expression. E1–6: Representative Masson trichrome staining and Picrosirius red staining. F–H: Quantitative analyses of CVF, collagen content, and PVCA/LA. Data are mean ± SEM; n = 7–10 per group. (A high-quality digital representation of this figure is available in the online issue.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Show All Figures
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Figure 7: TRB3 gene therapy decreases myocardial hypertrophy and fibrosis in HF and diabetic (DM) groups. 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 section of LV stained with H&E (scale bar: 50 μm). B–D: Quantitative data for heart weight to body weight (HW-to-BW) ratio, myocyte size, and relative brain natriuretic protein (BNP) mRNA expression. E1–6: Representative Masson trichrome staining and Picrosirius red staining. F–H: Quantitative analyses of CVF, collagen content, and PVCA/LA. Data are mean ± SEM; n = 7–10 per group. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: With TRB3-siRNA treatment, heart weight-to-body weight ratio and myocyte size were significantly decreased in the diabetic versus the vehicle group (heart weight-to-body weight ratio: 2.67 ± 0.13 vs. 3.49 ± 0.36 mg/g, P < 0.05; myocyte size: 384.32 ± 8.69 vs. 440.14 ± 4.47 μm2, P < 0.01) (Fig. 7B and C). The mRNA expression of brain natriuretic protein was lower in both the HF and diabetic groups than in the vehicle control (P < 0.001) (Fig. 7D). CVF and PVCA/LA were reduced (P < 0.001, P < 0.01) (Fig. 7F and H). In addition, collagen content was lower in the diabetic group than the vehicle group (10.17 ± 0.41 vs. 13.84 ± 0.48 μg/mg LV weight, respectively; P < 0.001) (Fig. 7G). Likewise, CVF and PVCA/LA were decreased in the TRB3-siRNA HF group (P < 0.05, P < 0.01) (Fig. 7F and H). In keeping with these observations, the decreased IB% and increased CVIB acquired from the IBS of the LV reconfirmed the improved pathological manifestations (P < 0.05 ∼ P < 0.001) (Supplementary Table 4).

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