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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook_2014     Display Documents

ID: 682172.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook_2014
Deletion of Fn14 receptor protects from right heart fibrosis and dysfunction
Authors:Novoyatleva, T.; Schymura, Y.; Janssen, W.; Strobl, F.; Swiercz, J. M.; Patra, C.; Posern, G.; Wietelmann, A.; Zheng, T. S.; Schermuly, R. T.; Engel, F. B.
Date of Publication (YYYY-MM-DD):2013
Journal Abbrev.:Basic Res Cardiol
Issue / Number:2
Start Page:325
Audience:Not Specified
Abstract / Description:Pulmonary arterial hypertension (PAH) is a fatal disease for which no cure is yet available. The leading cause of death in PAH is right ventricular (RV) failure. Previously, the TNF receptor superfamily member fibroblast growth factor-inducible molecule 14 (Fn14) has been associated with different fibrotic diseases. However, so far there is no study demonstrating a causal role for endogenous Fn14 signaling in RV or LV heart disease. The purpose of this study was to determine whether global ablation of Fn14 prevents RV fibrosis and remodeling improving heart function. Here, we provide evidence for a causative role of Fn14 in pulmonary artery banding (PAB)-induced RV fibrosis and dysfunction in mice. Fn14 expression was increased in the RV after PAB. Mice lacking Fn14 (Fn14(-/-)) displayed substantially reduced RV fibrosis and dysfunction following PAB compared to wild-type littermates. Cell culture experiments demonstrated that activation of Fn14 induces collagen expression via RhoA-dependent nuclear translocation of myocardin-related transcription factor-A (MRTF-A)/MAL. Furthermore, activation of Fn14 in vitro caused fibroblast proliferation and myofibroblast differentiation, which corresponds to suppression of PAB-induced RV fibrosis in Fn14(-/-) mice. Moreover, our findings suggest that Fn14 expression is regulated by endothelin-1 (ET-1) in cardiac fibroblasts. We conclude that Fn14 is an endogenous key regulator in cardiac fibrosis and suggest this receptor as potential new target for therapeutic interventions in heart failure.
Free Keywords:Animals; Apoptosis Regulatory Proteins/genetics/metabolism; Blotting, Western; Cell Differentiation; Cell Proliferation; Collagen/metabolism; Endothelin-1/physiology; Fibrosis/prevention & control; Fluorescent Antibody Technique; Hypertension, Pulmonary/complications; Hypertrophy, Right Ventricular/metabolism/physiopathology/*prevention & control; Immunohistochemistry; Membrane Proteins/genetics/metabolism; Mice; Mice, Knockout; Myocardium/*pathology; Myofibroblasts; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptors, Tumor Necrosis Factor/*physiology; Signal Transduction; Trans-Activators/genetics/metabolism; Transcription Factors/genetics/metabolism; Tumor Necrosis Factors/genetics/metabolism; Up-Regulation; Ventricular Dysfunction, Right/metabolism/physiopathology/*prevention & control
External Publication Status:published
Document Type:Article
Communicated by:Svea Hümmer
Affiliations:MPI für physiologische und klinische Forschung
Identifiers:ISSN:1435-1803 (Electronic) 0300-8428 (Linking) %R 10.1007/s00395-012-0325-x
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