title: Tumor necrosis factor-alpha antagonism protects from myocardial inflammation and fibrosis in experimental diabetic cardiomyopathy.
abstract: 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.
authors.affiliation: Dept of Cardiology and Pneumonology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Westermann
authors.forename: Sophie
authors.initials: S
authors.lastname: Van Linthout
authors.forename: Sameer
authors.initials: S
authors.lastname: Dhayat
authors.forename: Nasser
authors.initials: N
authors.lastname: Dhayat
authors.forename: Andre
authors.initials: A
authors.lastname: Schmidt
authors.forename: Michel
authors.initials: M
authors.lastname: Noutsias
authors.forename: Xi-Yong
authors.initials: XY
authors.lastname: Song
authors.forename: Frank
authors.initials: F
authors.lastname: Spillmann
authors.forename: Alexander
authors.initials: A
authors.lastname: Riad
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschöpe
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure / Q000502:physiology; D009202:Cardiomyopathies / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D048909:Diabetes Complications / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism / Q000517:prevention & control; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D009205:Myocarditis / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control
chemical_list: D000911:Antibodies, Monoclonal; D024042:Collagen Type I; D024061:Collagen Type III; D016207:Cytokines; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D013311:Streptozocin; D048049:Extracellular Signal-Regulated MAP Kinases