TRB3 Gene Silencing Alleviates Diabetic Cardiomyopathy in a Type 2 Diabetic Rat Model

• DOI: 10.2337/db11-0549
• Publication Date: 2011-09-21T03:47:26Z
• Authors: Yun Ti; Guo-lu Xie; Zhi-hao Wang; Xiao-lei Bi; Wen-yuan Ding; Jia Wang; Gui-hua Jiang; Pei-li Bu; Yun Zhang; Ming Zhong; Wei Zhang
• Keywords: Male; 0301 basic medicine; Diabetic Cardiomyopathies; MAP Kinase Signaling System; Myocardium; Heart; Genetic Therapy; Protein Serine-Threonine Kinases; Pathophysiology; Dietary Fats; Rats; 3. Good health; Disease Models, Animal; Random Allocation; 03 medical and health sciences; Diabetes Mellitus, Type 2; Animals; Gene Silencing; Insulin Resistance; Phosphorylation; RNA, Small Interfering; Protein Kinases; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt

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 NH2-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.