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Wnt5a is elevated in heart failure and affects cardiac fibroblast function

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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.

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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.

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Authors and Affiliations

  1. Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet; Postboks 4950 Nydalen, 0424, Oslo, Norway

    Aurelija Abraityte, Leif E. Vinge, Erik T. Askevold, Tove Lekva, Annika E. Michelsen, Trine Ranheim, Katrine Alfsnes, Christen P. Dahl, Pål Aukrust, Arne Yndestad & Thor Ueland

  2. Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Postboks 1078 Blindern, 0316, Oslo, Norway

    Aurelija Abraityte, Annika E. Michelsen, Arnt Fiane, Pål Aukrust, Lars Gullestad, Arne Yndestad & Thor Ueland

  3. Center for Heart Failure Research, University of Oslo, Postboks 1078 Blindern, 0316, Oslo, Norway

    Aurelija Abraityte, Leif E. Vinge, Erik T. Askevold, Ida G. Lunde, Christen P. Dahl, Geir Christensen, Lars Gullestad & Arne Yndestad

  4. Department of Medicine, Diakonhjemmet Hospital, Postboks 23 Vinderen, 0319, Oslo, Norway

    Leif E. Vinge

  5. Department of Cardiothoracic Surgery, Oslo University Hospital, Rikshospitalet; Postboks 4950 Nydalen, 0424, Oslo, Norway

    Arnt Fiane

  6. Department of Cardiology, Oslo University Hospital, Rikshospitalet; Postboks 4950 Nydalen, 0424, Oslo, Norway

    Svend Aakhus, Christen P. Dahl & Lars Gullestad

  7. Department of Circulation and Imaging, Faculty of Medicine, Norwegian University of Science and Technology, Postboks 8905 NTNU, Faculty of Medicine, 7491, Trondheim, Norway

    Svend Aakhus

  8. Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Postboks 4956 Nydalen, 0424, Oslo, Norway

    Ida G. Lunde & Geir Christensen

  9. K. G. Jebsen Inflammation Research Center, University of Oslo, Postboks 1078 Blindern, 0316, Oslo, Norway

    Pål Aukrust & Arne Yndestad

  10. Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet; Postboks 4950 Nydalen, 0424, Oslo, Norway

    Pål Aukrust

  11. K. G. Jebsen Thrombosis Research and Expertise Center, The Arctic University of Norway, Postboks 6050 Langnes, 9037, Tromsø, Norway

    Pål Aukrust & Thor Ueland

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  1. Aurelija Abraityte
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  2. Leif E. Vinge
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Correspondence to Aurelija Abraityte.

Ethics declarations

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).

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The authors declare that they have no competing interests.

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Abraityte, A., Vinge, L.E., Askevold, E.T. et al. Wnt5a is elevated in heart failure and affects cardiac fibroblast function. J Mol Med 95, 767–777 (2017). https://doi.org/10.1007/s00109-017-1529-1

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