title: Transforming growth factor-beta receptor antagonism attenuates myocardial fibrosis in mice with cardiac-restricted overexpression of tumor necrosis factor.
abstract: The mechanisms that are responsible for the development of myocardial fibrosis in inflammatory cardiomyopathy are unknown. We have previously generated lines of transgenic mice with cardiac-restricted overexpression of tumor necrosis factor (MHCsTNF mice), a pro-inflammatory cytokine. The MHCsTNF mice develop a heart failure phenotype that is characterized by progressive myocardial fibrosis, as well as increased levels transforming growth factor-beta (TGF-beta)(mRNA and protein. In order to determine whether TGF-beta-mediated signaling was responsible for the myocardial fibrosis observed in the MHCsTNF mice, we treated MHCsTNF and littermate control mice from 4 to 12 weeks of age with a novel orally available TGF-beta receptor antagonist (NP-40208). At the time of terminal study, myocardial collagen content was determined using the picrosirius red technique, and left ventricular (LV) systolic and diastolic function were determined using the Langendorff method. Treatment with NP-40208 resulted in a significant (P < 0.05) 65% decrease in nuclear translocation of Smad 2/3, a significant (P < 0.05), decrease in the heart-weight to body-weight ratio from 6.5 to 5.7, a approximately 37% decrease in fibrillar collagen content (P < 0.01) and a significant (P < 0.05) decrease in the LV chamber stiffness by approximately 25% in the MHCsTNF mice when compared to diluent-treated controls. Treatment with NP-40208 had no discernable effect on LV systolic function, nor any effect on cardiac myocyte size or fetal gene expression in the MHCsTNF mice. Taken together, these observations suggest that sustained pro-inflammatory signaling in the adult heart is associated with a pro-fibrotic phenotype that arises, at least in part, from TGF-beta-mediated signaling, with resultant activation of Smad 2/3, leading to increased myocardial fibrosis and increased LV diastolic chamber stiffness.
authors.affiliation: Section of Cardiology, Department of Medicine, Winters Center for Heart Failure Research, Houston, TX, USA.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sakata
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Chancey
authors.forename: Vijay G
authors.initials: VG
authors.lastname: Divakaran
authors.forename: Kenichi
authors.initials: K
authors.lastname: Sekiguchi
authors.forename: Natarajan
authors.initials: N
authors.lastname: Sivasubramanian
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Mann
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D006332:Cardiomegaly / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005333:Fetus / Q000378:metabolism; D024022:Fibrillar Collagens / Q000378:metabolism; D005355:Fibrosis / Q000473:pathology / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011621:Pteridines / Q000494:pharmacology*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D051899:Smad2 Protein / Q000378:metabolism / Q000502:physiology; D051900:Smad3 Protein / Q000378:metabolism / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
chemical_list: D024022:Fibrillar Collagens; C529989:NP 40208; D011621:Pteridines; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I