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Open Access 01-03-2013 | Original Contribution

Deletion of Fn14 receptor protects from right heart fibrosis and dysfunction

Authors: Tatyana Novoyatleva, Yves Schymura, Wiebke Janssen, Frederic Strobl, Jakub M. Swiercz, Chinmoy Patra, Guido Posern, Astrid Wietelmann, Timothy S. Zheng, Ralph T. Schermuly, Felix B. Engel

Published in: Basic Research in Cardiology | Issue 2/2013

Abstract

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.

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Title: Deletion of Fn14 receptor protects from right heart fibrosis and dysfunction
Authors: Tatyana Novoyatleva
Yves Schymura
Wiebke Janssen
Frederic Strobl
Jakub M. Swiercz
Chinmoy Patra
Guido Posern
Astrid Wietelmann
Timothy S. Zheng
Ralph T. Schermuly
Felix B. Engel
Publication date: 01-03-2013
Publisher: Springer-Verlag
Published in: Basic Research in Cardiology / Issue 2/2013
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-012-0325-x

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