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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

Deterioration of cardiac function in diabetic (DM) rats. A1: Representative two-dimensional echocardiograms. A2: Representative M-mode echocardiograms. A3: Representative pulsed-wave Doppler echocardiograms of mitral inflow. A4: Representative tissue Doppler echocardiograms. B–F: Sequential evaluations of left ventricular end diastolic diameter (LVEDd) (B), LVEF (C), FS (D), E/A (E), and E′/A′ (F). G: Electrocardiogram of control and DM groups at the end of the experiment. H: Pressure curves of cardiac catheterization. I: Analysis of LVEDP. Data are mean ± SEM; n = 7–10 per group. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control; †P < 0.05 vs. HF. w, weeks. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 2: Deterioration of cardiac function in diabetic (DM) rats. A1: Representative two-dimensional echocardiograms. A2: Representative M-mode echocardiograms. A3: Representative pulsed-wave Doppler echocardiograms of mitral inflow. A4: Representative tissue Doppler echocardiograms. B–F: Sequential evaluations of left ventricular end diastolic diameter (LVEDd) (B), LVEF (C), FS (D), E/A (E), and E′/A′ (F). G: Electrocardiogram of control and DM groups at the end of the experiment. H: Pressure curves of cardiac catheterization. I: Analysis of LVEDP. Data are mean ± SEM; n = 7–10 per group. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control; †P < 0.05 vs. HF. w, weeks. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: We evaluated ejection fraction, FS, E/A, and E′/A′ to investigate changes in systolic and diastolic function. Similar to the pattern in humans, in rats, diastolic dysfunction precedes systolic dysfunction, beginning from 2 to 3 months after the induction of diabetes (26). In our study, at 6 weeks after the onset of diabetes (at week 11), the diabetic rats showed a moderate decrease in E/A and E′/A′ compared with the control (P < 0.05) (Fig. 2E and F); LVEF and FS were impaired from week 17 (Fig. 2C and D). At the end of the experiment, LVEF, FS, E/A, and E′/A′ were further decreased in the diabetic group, with the reduction in E/A and E′/A′ more pronounced. LVEF, FS, E/A, and E′/A′ were also reduced in the chow + STZ group compared with the control (P < 0.05) (Fig. 2C–F) at the end of the experiment. Left ventricular end-diastolic diameter was the highest in the diabetic group (Fig. 2B).


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)

Deterioration of cardiac function in diabetic (DM) rats. A1: Representative two-dimensional echocardiograms. A2: Representative M-mode echocardiograms. A3: Representative pulsed-wave Doppler echocardiograms of mitral inflow. A4: Representative tissue Doppler echocardiograms. B–F: Sequential evaluations of left ventricular end diastolic diameter (LVEDd) (B), LVEF (C), FS (D), E/A (E), and E′/A′ (F). G: Electrocardiogram of control and DM groups at the end of the experiment. H: Pressure curves of cardiac catheterization. I: Analysis of LVEDP. Data are mean ± SEM; n = 7–10 per group. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control; †P < 0.05 vs. HF. 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
Show All Figures
getmorefigures.php?uid=PMC3198078&req=5

Figure 2: Deterioration of cardiac function in diabetic (DM) rats. A1: Representative two-dimensional echocardiograms. A2: Representative M-mode echocardiograms. A3: Representative pulsed-wave Doppler echocardiograms of mitral inflow. A4: Representative tissue Doppler echocardiograms. B–F: Sequential evaluations of left ventricular end diastolic diameter (LVEDd) (B), LVEF (C), FS (D), E/A (E), and E′/A′ (F). G: Electrocardiogram of control and DM groups at the end of the experiment. H: Pressure curves of cardiac catheterization. I: Analysis of LVEDP. Data are mean ± SEM; n = 7–10 per group. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control; †P < 0.05 vs. HF. w, weeks. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: We evaluated ejection fraction, FS, E/A, and E′/A′ to investigate changes in systolic and diastolic function. Similar to the pattern in humans, in rats, diastolic dysfunction precedes systolic dysfunction, beginning from 2 to 3 months after the induction of diabetes (26). In our study, at 6 weeks after the onset of diabetes (at week 11), the diabetic rats showed a moderate decrease in E/A and E′/A′ compared with the control (P < 0.05) (Fig. 2E and F); LVEF and FS were impaired from week 17 (Fig. 2C and D). At the end of the experiment, LVEF, FS, E/A, and E′/A′ were further decreased in the diabetic group, with the reduction in E/A and E′/A′ more pronounced. LVEF, FS, E/A, and E′/A′ were also reduced in the chow + STZ group compared with the control (P < 0.05) (Fig. 2C–F) at the end of the experiment. Left ventricular end-diastolic diameter was the highest in the diabetic group (Fig. 2B).

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