Journal of Molecular Medicine

, Volume 95, Issue 7, pp 767–777 | Cite as

Wnt5a is elevated in heart failure and affects cardiac fibroblast function

  • Aurelija Abraityte
  • Leif E. Vinge
  • Erik T. Askevold
  • Tove Lekva
  • Annika E. Michelsen
  • Trine Ranheim
  • Katrine Alfsnes
  • Arnt Fiane
  • Svend Aakhus
  • Ida G. Lunde
  • Christen P. Dahl
  • Pål Aukrust
  • Geir Christensen
  • Lars Gullestad
  • Arne Yndestad
  • Thor Ueland
Original Article

Abstract

Wnt signaling is dysregulated in heart failure (HF) and may promote cardiac hypertrophy, fibrosis, and inflammation. Blocking the Wnt ligand Wnt5a prevents HF in animal models. However, the role of Wnt5a in human HF and its functions in cardiac cells remain unclear. Here, we investigated Wnt5a regulation in HF patients and its effects on primary mouse and human cardiac fibroblasts. Serum Wnt5a was elevated in HF patients and associated with hemodynamic, neurohormonal, and clinical measures of disease severity. In failing human hearts, Wnt5a protein correlated with interleukin (IL)-6 and tissue inhibitor of metalloproteinase (TIMP)-1. Wnt5a messenger RNA (mRNA) levels were markedly upregulated in failing myocardium and both mRNA and protein levels declined following left ventricular assist device therapy. In primary mouse and human cardiac fibroblasts, recombinant Wnt5a dose-dependently upregulated mRNA and protein release of IL-6 and TIMP-1. Wnt5a did not affect β-catenin levels, but activated extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. Importantly, inhibition of ERK1/2 activation attenuated Wnt5a-induced release of IL-6 and TIMP-1. In conclusion, our results show that Wnt5a is elevated in the serum and myocardium of HF patients and is associated with measures of progressive HF. Wnt5a induces IL-6 and TIMP-1 in cardiac fibroblasts, which might promote myocardial inflammation and fibrosis, and thereby contribute to HF progression.

Key messages

• Wnt5a is elevated in serum and myocardium of HF patients and is associated with measures of progressive HF.

• In cardiac fibroblasts, Wnt5a upregulates interleukin (IL)-6 and tissue inhibitor of metalloproteinase (TIMP)-1 through the ERK pathway.

• Wnt5a-mediated effects might promote myocardial inflammation and fibrosis, and thereby contribute to HF progression.

Keywords

Wnt5a Wnt signaling Heart failure Il-6 TIMP-1 ERK 

Notes

Acknowledgements

We are grateful to the patients and the animal facility staff at Oslo University Hospital, Oslo, Norway, for contributing to our research.

This work was supported by the South-Eastern Norway Regional Health Authority [grant number 2013041], the Research Council of Norway, Anders Jahre’s Fund for the Promotion of Science, Norway, and the Simon Fougner Hartmanns Family Fund, Denmark.

Compliance with ethical standards

Human studies conformed to the Declaration of Helsinki and were approved by the South Eastern Regional Committee for Medical and Health Research Ethics. Written informed consent was obtained from all individuals. Animal experiments were approved by the animal research committee and were carried out in accordance with institutional guidelines and conformed to the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institutes of Health (NIH Publication No. 85-23, revised 2011).

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

109_2017_1529_MOESM1_ESM.pdf (440 kb)
ESM 1 (PDF 439 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Aurelija Abraityte
    • 1
    • 2
    • 3
  • Leif E. Vinge
    • 1
    • 3
    • 4
  • Erik T. Askevold
    • 1
    • 3
  • Tove Lekva
    • 1
  • Annika E. Michelsen
    • 1
    • 2
  • Trine Ranheim
    • 1
  • Katrine Alfsnes
    • 1
  • Arnt Fiane
    • 2
    • 5
  • Svend Aakhus
    • 6
    • 7
  • Ida G. Lunde
    • 3
    • 8
  • Christen P. Dahl
    • 1
    • 3
    • 6
  • Pål Aukrust
    • 1
    • 2
    • 9
    • 10
    • 11
  • Geir Christensen
    • 3
    • 8
  • Lars Gullestad
    • 2
    • 3
    • 6
  • Arne Yndestad
    • 1
    • 2
    • 3
    • 9
  • Thor Ueland
    • 1
    • 2
    • 11
  1. 1.Research Institute of Internal MedicineOslo University HospitalOsloNorway
  2. 2.Institute of Clinical Medicine, Faculty of MedicineUniversity of OsloOsloNorway
  3. 3.Center for Heart Failure ResearchUniversity of OsloOsloNorway
  4. 4.Department of MedicineDiakonhjemmet HospitalOsloNorway
  5. 5.Department of Cardiothoracic SurgeryOslo University HospitalOsloNorway
  6. 6.Department of CardiologyOslo University HospitalOsloNorway
  7. 7.Department of Circulation and Imaging, Faculty of MedicineNorwegian University of Science and TechnologyTrondheimNorway
  8. 8.Institute for Experimental Medical ResearchOslo University Hospital and University of OsloOsloNorway
  9. 9.K. G. Jebsen Inflammation Research CenterUniversity of OsloOsloNorway
  10. 10.Section of Clinical Immunology and Infectious DiseasesOslo University HospitalOsloNorway
  11. 11.K. G. Jebsen Thrombosis Research and Expertise CenterThe Arctic University of NorwayTromsøNorway

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