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Follistatin-Like 3 Mediates Paracrine Fibroblast Activation by Cardiomyocytes

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Abstract

Follistatins are extracellular inhibitors of the TGF-β family ligands including activin A, myostatin and bone morphogenetic proteins. Follistatin-like 3 (FSTL3) is a potent inhibitor of activin signalling and antagonises the cardioprotective role of activin A in the heart. FSTL3 expression is elevated in patients with heart failure and is upregulated in cardiomyocytes by hypertrophic stimuli, but its role in cardiac remodelling is largely unknown. Here, we show that the production of FSTL3 by cardiomyocytes contributes to the paracrine activation of cardiac fibroblasts, inducing changes in cell adhesion, promoting proliferation and increasing collagen production. We found that FSTL3 is necessary for this response and for the induction of cardiac fibrosis. However, full activation requires additional factors, and we identify connective tissue growth factor as a FSTL3 binding partner in this process. Together, our data unveil a novel mechanism of paracrine communication between cardiomyocytes and fibroblasts that may provide potential as a therapeutic target in heart remodelling.

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Acknowledgments

This work was supported by a British Heart Foundation grant (PG/08/084/25827) to P.B., N.R. and E.L.P. In addition, PB was supported by Heart Research UK and by the National Institute for Health Research Cardiovascular Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College. E.L.P. was supported by grants from the European Union (ERG-239158, ITN-289600), the Spanish Ministry of Science and Innovation (BFU2009-10016, CP08/00144) and the Regional Government of Madrid (S2010/BMD-2321 ‘Fibroteam’).

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Authors and Affiliations

  1. Heart Science Centre, Imperial College London, Hill End Road, Middlesex, UB9 6JH, UK

    Kalyani D. Panse, Leanne E. Felkin, Paul J. R. Barton, Nadia Rosenthal & Enrique Lara-Pezzi

  2. Cardiovascular Development and Repair Department, Fundación Centro Nacional de Investigaciones Cardiovasculares, Melchor Fernandez Almagro, 3, 28029, Madrid, Spain

    Marina M. López-Olañeta, Jesús Gómez-Salinero, María Villalba, Lucía Muñoz & Enrique Lara-Pezzi

  3. Whitaker Cardiovascular Institute, Boston University Medical Campus, Boston, MA, 02118, USA

    Kazuto Nakamura, Masayuki Shimano & Kenneth Walsh

  4. NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust, London, UK

    Paul J. R. Barton

  5. Australian Regenerative Medicine Institute, Monash University, Melbourne, Australia

    Nadia Rosenthal

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  1. Kalyani D. Panse
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  2. Leanne E. Felkin
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Correspondence to Enrique Lara-Pezzi.

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Panse, K.D., Felkin, L.E., López-Olañeta, M.M. et al. Follistatin-Like 3 Mediates Paracrine Fibroblast Activation by Cardiomyocytes. J. of Cardiovasc. Trans. Res. 5, 814–826 (2012). https://doi.org/10.1007/s12265-012-9400-9

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