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Journal of Cardiovascular Translational Research

, Volume 5, Issue 6, pp 814–826 | Cite as

Follistatin-Like 3 Mediates Paracrine Fibroblast Activation by Cardiomyocytes

  • Kalyani D. Panse
  • Leanne E. Felkin
  • Marina M. López-Olañeta
  • Jesús Gómez-Salinero
  • María Villalba
  • Lucía Muñoz
  • Kazuto Nakamura
  • Masayuki Shimano
  • Kenneth Walsh
  • Paul J. R. Barton
  • Nadia Rosenthal
  • Enrique Lara-Pezzi
Article

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.

Keywords

FSTL3 Follistatins Paracrine activation Cardiac fibroblast CTGF 

Notes

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’).

Supplementary material

12265_2012_9400_MOESM1_ESM.pdf (828 kb)
ESM 1 (PDF 828 kb)

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Kalyani D. Panse
    • 1
  • Leanne E. Felkin
    • 1
  • Marina M. López-Olañeta
    • 2
  • Jesús Gómez-Salinero
    • 2
  • María Villalba
    • 2
  • Lucía Muñoz
    • 2
  • Kazuto Nakamura
    • 3
  • Masayuki Shimano
    • 3
  • Kenneth Walsh
    • 3
  • Paul J. R. Barton
    • 1
    • 4
  • Nadia Rosenthal
    • 1
    • 5
  • Enrique Lara-Pezzi
    • 1
    • 2
  1. 1.Heart Science Centre, Imperial College LondonMiddlesexUK
  2. 2.Cardiovascular Development and Repair DepartmentFundación Centro Nacional de Investigaciones CardiovascularesMadridSpain
  3. 3.Whitaker Cardiovascular InstituteBoston University Medical CampusBostonUSA
  4. 4.NIHR Cardiovascular Biomedical Research UnitRoyal Brompton and Harefield NHS Foundation TrustLondonUK
  5. 5.Australian Regenerative Medicine InstituteMonash UniversityMelbourneAustralia

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