title: Wnt5a is elevated in heart failure and affects cardiac fibroblast function.
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.
  
  
  
  • 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.
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet; Postboks 4950 Nydalen, 0424, Oslo, Norway. Aurelija.abraityte@rr-research.no.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Postboks 1078 Blindern, 0316, Oslo, Norway. Aurelija.abraityte@rr-research.no.|Center for Heart Failure Research, University of Oslo, Postboks 1078 Blindern, 0316, Oslo, Norway. Aurelija.abraityte@rr-research.no.
authors.forename: Aurelija
authors.identifier: 0000-0002-7584-3163
authors.initials: A
authors.lastname: Abraityte
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet; Postboks 4950 Nydalen, 0424, Oslo, Norway.|Center for Heart Failure Research, University of Oslo, Postboks 1078 Blindern, 0316, Oslo, Norway.|Department of Medicine, Diakonhjemmet Hospital, Postboks 23 Vinderen, 0319, Oslo, Norway.
authors.forename: Leif E
authors.initials: LE
authors.lastname: Vinge
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet; Postboks 4950 Nydalen, 0424, Oslo, Norway.|Center for Heart Failure Research, University of Oslo, Postboks 1078 Blindern, 0316, Oslo, Norway.
authors.forename: Erik T
authors.initials: ET
authors.lastname: Askevold
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet; Postboks 4950 Nydalen, 0424, Oslo, Norway.
authors.forename: Tove
authors.initials: T
authors.lastname: Lekva
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet; Postboks 4950 Nydalen, 0424, Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Postboks 1078 Blindern, 0316, Oslo, Norway.
authors.forename: Annika E
authors.initials: AE
authors.lastname: Michelsen
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet; Postboks 4950 Nydalen, 0424, Oslo, Norway.
authors.forename: Trine
authors.initials: T
authors.lastname: Ranheim
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet; Postboks 4950 Nydalen, 0424, Oslo, Norway.
authors.forename: Katrine
authors.initials: K
authors.lastname: Alfsnes
authors.affiliation: Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Postboks 1078 Blindern, 0316, Oslo, Norway.|Department of Cardiothoracic Surgery, Oslo University Hospital, Rikshospitalet; Postboks 4950 Nydalen, 0424, Oslo, Norway.
authors.forename: Arnt
authors.initials: A
authors.lastname: Fiane
authors.affiliation: Department of Cardiology, Oslo University Hospital, Rikshospitalet; Postboks 4950 Nydalen, 0424, Oslo, Norway.|Department of Circulation and Imaging, Faculty of Medicine, Norwegian University of Science and Technology, Postboks 8905 NTNU, Faculty of Medicine, 7491, Trondheim, Norway.
authors.forename: Svend
authors.initials: S
authors.lastname: Aakhus
authors.affiliation: Center for Heart Failure Research, University of Oslo, Postboks 1078 Blindern, 0316, Oslo, Norway.|Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Postboks 4956 Nydalen, 0424, Oslo, Norway.
authors.forename: Ida G
authors.initials: IG
authors.lastname: Lunde
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet; Postboks 4950 Nydalen, 0424, Oslo, Norway.|Center for Heart Failure Research, University of Oslo, Postboks 1078 Blindern, 0316, Oslo, Norway.|Department of Cardiology, Oslo University Hospital, Rikshospitalet; Postboks 4950 Nydalen, 0424, Oslo, Norway.
authors.forename: Christen P
authors.initials: CP
authors.lastname: Dahl
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet; Postboks 4950 Nydalen, 0424, Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Postboks 1078 Blindern, 0316, Oslo, Norway.|K. G. Jebsen Inflammation Research Center, University of Oslo, Postboks 1078 Blindern, 0316, Oslo, Norway.|Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet; Postboks 4950 Nydalen, 0424, Oslo, Norway.|K. G. Jebsen Thrombosis Research and Expertise Center, The Arctic University of Norway, Postboks 6050 Langnes, 9037, Tromsø, Norway.
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.affiliation: Center for Heart Failure Research, University of Oslo, Postboks 1078 Blindern, 0316, Oslo, Norway.|Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Postboks 4956 Nydalen, 0424, Oslo, Norway.
authors.forename: Geir
authors.initials: G
authors.lastname: Christensen
authors.affiliation: Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Postboks 1078 Blindern, 0316, Oslo, Norway.|Center for Heart Failure Research, University of Oslo, Postboks 1078 Blindern, 0316, Oslo, Norway.|Department of Cardiology, Oslo University Hospital, Rikshospitalet; Postboks 4950 Nydalen, 0424, Oslo, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Gullestad
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet; Postboks 4950 Nydalen, 0424, Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Postboks 1078 Blindern, 0316, Oslo, Norway.|Center for Heart Failure Research, University of Oslo, Postboks 1078 Blindern, 0316, Oslo, Norway.|K. G. Jebsen Inflammation Research Center, University of Oslo, Postboks 1078 Blindern, 0316, Oslo, Norway.
authors.forename: Arne
authors.initials: A
authors.lastname: Yndestad
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet; Postboks 4950 Nydalen, 0424, Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Postboks 1078 Blindern, 0316, Oslo, Norway.|K. G. Jebsen Thrombosis Research and Expertise Center, The Arctic University of Norway, Postboks 6050 Langnes, 9037, Tromsø, Norway.
authors.forename: Thor
authors.initials: T
authors.lastname: Ueland
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006333:Heart Failure / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D060449:Wnt Signaling Pathway; D000071818:Wnt-5a Protein / Q000097:blood / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D019715:Tissue Inhibitor of Metalloproteinase-1; D000071818:Wnt-5a Protein
keywords: ERK; Heart failure; Il-6; TIMP-1; Wnt signaling; Wnt5a