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

Abstract

OBJECTIVETribbles 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 METHODSThe 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.RESULTSRats 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.

Sitagliptin alleviated myocardial remodeling of the left ventricle and improved cardiac diastolic dysfunction in diabetic rats

“…It reversed the altered blood glucose, HbA 1 and lipid levels, and plasma GLP-1 and insulin levels, and reduced fat deposition in diabetic myocardial and epicardial tissues, so sitagliptin may play an essential role in improving diabetic cardiac dysfunction and cardiomyopathy. Inflammation is a key pathophysiologic factor in diabetic cardiomyopathy (1,2,16,21), and is closely related to fat deposition. Ti et al (16) reported that TNF-a and IL-6 were overexpressed in diabetic rats.…”

“…Inflammation is a key pathophysiologic factor in diabetic cardiomyopathy (1,2,16,21), and is closely related to fat deposition. Ti et al (16) reported that TNF-a and IL-6 were overexpressed in diabetic rats. Biomarkers of inflammation including TNF-a and IL-6 levels are associated with risk of developing type 2 diabetes.…”

“…Fasting insulin and fasting blood glucose (FBG) were measured, and the insulin sensitivity index [ISI ¼ ln (FBG Â fasting insulin) À1 ] was calculated. Control rats received citrate buffer (intraperitoneally) alone and rats with insulin resistance received a single intraperitoneal injection of STZ (Sigma, St. Louis, MO; 30 mg/kg intraperitoneally in 0.1 mol/L citrate buffer, pH 4.5) as described (16). At one week after STZ administration, rats with FBG > 11.1 mmol/L in 2 consecutive analyses were considered the diabetic model.…”

“…Wall thickness and LV dimensions, including LV end systolic diameter (LVEDs) and LV end diastolic diameter (LVEDd), were obtained from the long-axis view. LV ejection fraction (LVEF) and fractional shortening (FS) were measured according to American Society of Echocardiography guidelines (16,17). The mitral-valve pulsed Doppler recordings were obtained from the apical fourchamber view.…”

Tribbles Homolog 3 Attenuates Mammalian Target of Rapamycin Complex-2 Signaling and Inflammation in the Diabetic Kidney

“…Thus, improvements in diabetic cardiomyopathy and atherosclerosis in type 2 diabetes could have been related to improved metabolic control. 61,62 mTOR is a conserved serine/threonine kinase modulated by growth factors and cellular energy status. It forms two distinct molecular complexes known as mTOR complex 1 (mTORC1) and mTORC2.…”