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Basic Research in Cardiology (1)
Development (Cambridge, England) (1)
Engel, Felix B. (2)
Novoyatleva, Tatyana (2)
Patra, Chinmoy (2)
Diehl, Florian (1)
Ferrazzi, Fulvia (1)
Janssen, Wiebke (1)
Jungblut, Benno (1)
Mühlfeld, Christian (1)
Posern, Guido (1)
Schaefer, Liliana (1)
Schermuly, Ralph T. (1)
Schymura, Yves (1)
Strobl, Frederic (1)
Swiercz, Jakub M. (1)
Wietelmann, Astrid (1)
Zheng, Timothy S. (1)
van Amerongen, Machteld J. (1)
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Deletion of Fn14 receptor protects from right heart fibrosis and dysfunction
Swiercz, Jakub M.
Zheng, Timothy S.
Schermuly, Ralph T.
Engel, Felix B.
Basic Research in Cardiology
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.
Electronic supplementary material
The online version of this article (doi:10.1007/s00395-012-0325-x) contains supplementary material, which is available to authorized users.
Right heart disease; Fibrosis; Fn14; MAL; Cardiac fibroblasts
Nephronectin regulates atrioventricular canal differentiation via Bmp4-Has2 signaling in zebrafish
van Amerongen, Machteld J.
Engel, Felix B.
Development (Cambridge, England)
The extracellular matrix is crucial for organogenesis. It is a complex and dynamic component that regulates cell behavior by modulating the activity, bioavailability and presentation of growth factors to cell surface receptors. Here, we determined the role of the extracellular matrix protein Nephronectin (Npnt) in heart development using the zebrafish model system. The vertebrate heart is formed as a linear tube in which myocardium and endocardium are separated by a layer of extracellular matrix termed the cardiac jelly. During heart development, the cardiac jelly swells at the atrioventricular (AV) canal, which precedes valve formation. Here, we show that Npnt expression correlates with this process. Morpholino-mediated knockdown of Npnt prevents proper valve leaflet formation and trabeculation and results in greater than 85% lethality at 7 days post-fertilization. The earliest observed phenotype is an extended tube-like structure at the AV boundary. In addition, the expression of myocardial genes involved in cardiac valve formation (cspg2, fibulin 1, tbx2b, bmp4) is expanded and endocardial cells along the extended tube-like structure exhibit characteristics of AV cells (has2, notch1b and Alcam expression, cuboidal cell shape). Inhibition of has2 in npnt morphants rescues the endocardial, but not the myocardial, expansion. By contrast, reduction of BMP signaling in npnt morphants reduces the ectopic expression of myocardial and endocardial AV markers. Taken together, our results identify Npnt as a novel upstream regulator of Bmp4-Has2 signaling that plays a crucial role in AV canal differentiation.
Nephronectin; Atrioventricular canal; Bmp4; Zebrafish
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