Tumor necrosis factor-alpha antagonism protects from myocardial inflammation and fibrosis in experimental diabetic cardiomyopathy

Basic Res Cardiol. 2007 Nov;102(6):500-7. doi: 10.1007/s00395-007-0673-0. Epub 2007 Oct 5.


To investigate the effect of anti-cytokine-based therapy in the course of diabetic cardiomyopathy, we performed a study using an anti-TNF-alpha monoclonal antibody treatment (mab) in Sprague male Dawley (SD) rats with streptozotocin-induced diabetic cardiomyopathy. Five days after streptozotocin injection, rats were treated with the anti-TNF-alpha mAb C432A for 6 weeks.At the end of the study, left ventricular (LV) function was determined by a pressure-catheter. Intercellular adhesion molecule (ICAM)-1, vascular adhesion molecule (VCAM)-1, beta2-lymphocyte-integrins(+) (CD18(+), CD11a(+), CD11b(+)), ED1/CD68(+) and cytokine (TNF-alpha, interleukin (IL)-1beta)- expressing infiltrates, total collagen content and stainings of collagen I and III were quantified by digital image analysis. LV phosphorylated and total ERK protein levels were determined by Western Blot. TNFalpha-antagonism reduced ICAM-1- and VCAM-1 expression and leukocyte infiltration to levels of non-diabetics and decreased macrophage residence by 3.3-fold compared with untreated diabetics. In addition, anti-TNF-alpha mAb-treatment decreased diabetes-induced cardiac TNF-alpha and IL-1beta expression by 2.0-fold and 1.8- fold, respectively, and reduced the ratio of phosphorylated to total ERK by 2.7-fold. The reduction in intramyocardial inflammation was associated with a 5.4-fold and 3.6-fold reduction in cardiac collagen I and III content, respectively. This was reflected by a normalization of cardiac total collagen content to levels of non-diabetics and associated with an improved LV function. TNFalpha-antagonism attenuates the development of experimental diabetic cardiomyopathy associated with a reduction of intramyocardial inflammation and cardiac fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use
  • Blood Pressure / physiology
  • Cardiomyopathies / metabolism
  • Cardiomyopathies / pathology
  • Cardiomyopathies / prevention & control*
  • Collagen Type I / metabolism
  • Collagen Type III / metabolism
  • Cytokines / metabolism
  • Diabetes Complications / metabolism
  • Diabetes Complications / pathology
  • Diabetes Complications / prevention & control*
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Experimental / pathology
  • Disease Models, Animal
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fibrosis / metabolism
  • Fibrosis / prevention & control
  • Interleukin-1beta / metabolism
  • Male
  • Myocarditis / metabolism
  • Myocarditis / prevention & control*
  • Myocardium / metabolism
  • Myocardium / pathology*
  • Rats
  • Rats, Sprague-Dawley
  • Streptozocin
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism
  • Ventricular Dysfunction, Left / metabolism
  • Ventricular Dysfunction, Left / pathology
  • Ventricular Dysfunction, Left / prevention & control


  • Antibodies, Monoclonal
  • Collagen Type I
  • Collagen Type III
  • Cytokines
  • Interleukin-1beta
  • Tumor Necrosis Factor-alpha
  • Streptozocin
  • Extracellular Signal-Regulated MAP Kinases