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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 improves cardiac function in diabetic (DM) rats. A: Relative mRNA expression and protein content of myocardial TRB3 in gene-silencing groups. B: Representative echocardiograms. C–G: Sequential evaluations of left ventricular end diastolic diameter (LVEDd) (C), FS (D), LVEF (E), E/A (F), and E′/A′ (G). H: Pressure curves of cardiac catheterization. I: Analysis of LVEDP with TRB3-siRNA silencing. Data are mean ± SEM; n = 7–10 per group. §P < 0.05, §§P < 0.01 vs. DM + vehicle. w, weeks. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 6: TRB3 gene therapy improves cardiac function in diabetic (DM) rats. A: Relative mRNA expression and protein content of myocardial TRB3 in gene-silencing groups. B: Representative echocardiograms. C–G: Sequential evaluations of left ventricular end diastolic diameter (LVEDd) (C), FS (D), LVEF (E), E/A (F), and E′/A′ (G). H: Pressure curves of cardiac catheterization. I: Analysis of LVEDP with TRB3-siRNA silencing. Data are mean ± SEM; n = 7–10 per group. §P < 0.05, §§P < 0.01 vs. DM + vehicle. w, weeks. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: When compared with vehicle treatment, TRB3-siRNA treatment conferred downregulated mRNA and protein expression of cardiac TRB3 (Fig. 6A). The mRNA and protein expression of hepatic TRB3 was also downregulated compared with the vehicles (Supplementary Fig. 2).


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 improves cardiac function in diabetic (DM) rats. A: Relative mRNA expression and protein content of myocardial TRB3 in gene-silencing groups. B: Representative echocardiograms. C–G: Sequential evaluations of left ventricular end diastolic diameter (LVEDd) (C), FS (D), LVEF (E), E/A (F), and E′/A′ (G). H: Pressure curves of cardiac catheterization. I: Analysis of LVEDP with TRB3-siRNA silencing. Data are mean ± SEM; n = 7–10 per group. §P < 0.05, §§P < 0.01 vs. DM + vehicle. w, weeks. (A high-quality digital representation of this figure is available in the online issue.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
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Figure 6: TRB3 gene therapy improves cardiac function in diabetic (DM) rats. A: Relative mRNA expression and protein content of myocardial TRB3 in gene-silencing groups. B: Representative echocardiograms. C–G: Sequential evaluations of left ventricular end diastolic diameter (LVEDd) (C), FS (D), LVEF (E), E/A (F), and E′/A′ (G). H: Pressure curves of cardiac catheterization. I: Analysis of LVEDP with TRB3-siRNA silencing. Data are mean ± SEM; n = 7–10 per group. §P < 0.05, §§P < 0.01 vs. DM + vehicle. w, weeks. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: When compared with vehicle treatment, TRB3-siRNA treatment conferred downregulated mRNA and protein expression of cardiac TRB3 (Fig. 6A). The mRNA and protein expression of hepatic TRB3 was also downregulated compared with the vehicles (Supplementary Fig. 2).

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