Skip to main content

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.

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.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. Liu L, Eisen HJ (2014) Epidemiology of heart failure and scope of the problem. Cardiol Clin 32:1–8 vii

    CAS  Article  PubMed  Google Scholar 

  2. Distefano G, Sciacca P (2012) Molecular pathogenesis of myocardial remodeling and new potential therapeutic targets in chronic heart failure. Ital J Pediatr 38:41

    Article  PubMed  PubMed Central  Google Scholar 

  3. ter Horst P, Smits JF, Blankesteijn WM (2012) The Wnt/frizzled pathway as a therapeutic target for cardiac hypertrophy: where do we stand? Acta Physiol (Oxf) 204:110–117

    Article  Google Scholar 

  4. Dawson K, Aflaki M, Nattel S (2013) Role of the Wnt-frizzled system in cardiac pathophysiology: a rapidly developing, poorly understood area with enormous potential. J Physiol 591:1409–1432

    Article  PubMed  Google Scholar 

  5. Tao H, Yang J-J, Shi K-H, Li J (2016) Wnt signaling pathway in cardiac fibrosis: new insights and directions. Metabolism 65:30–40

    CAS  Article  PubMed  Google Scholar 

  6. Lerner UH, Ohlsson C (2015) The WNT system: background and its role in bone. J Intern Med 277:630–649

    CAS  Article  PubMed  Google Scholar 

  7. Bikkavilli RK, Malbon CC (2009) Mitogen-activated protein kinases and Wnt/beta-catenin signaling: molecular conversations among signaling pathways. Commun Integr Biol 2:46–49

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Mikels AJ, Nusse R (2006) Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context. PLoS Biol 4:e115

    Article  PubMed  PubMed Central  Google Scholar 

  9. Kikuchi A, Yamamoto H, Sato A, Matsumoto S (2012) Wnt5a: its signalling, functions and implication in diseases. Acta Physiol (Oxf) 204:17–33

    CAS  Article  Google Scholar 

  10. Bhatt PM, Malgor R (2014) Wnt5a: a player in the pathogenesis of atherosclerosis and other inflammatory disorders. Atherosclerosis 237:155–162

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Hagenmueller M, Riffel JH, Bernhold E, Fan J, Katus HA, Hardt SE (2014) Dapper-1 is essential for Wnt5a induced cardiomyocyte hypertrophy by regulating the Wnt/PCP pathway. FEBS Lett 588:2230–2237

    CAS  Article  PubMed  Google Scholar 

  12. Laeremans H, Hackeng TM, van Zandvoort MA, Thijssen VL, Janssen BJ, Ottenheijm HC, Smits JF, Blankesteijn WM (2011) Blocking of frizzled signaling with a homologous peptide fragment of wnt3a/wnt5a reduces infarct expansion and prevents the development of heart failure after myocardial infarction. Circulation 124:1626–1635

    CAS  Article  PubMed  Google Scholar 

  13. Hermans K, Uitterdijk A, de Wijs-Meijler D, Daskalopoulos E, Verzijl A, Sneep S, Blonden L, Reiss I, Duncker D, Blankesteijn WM et al (2015) UM206, a Peptide Fragment of Wnt5a, Attenuates Adverse Remodeling after Myocardial Infarction in Swine. The FASEB Journal 29

  14. Newman DR, Sills WS, Hanrahan K, Ziegler A, Tidd KM, Cook E, Sannes PL (2016) Expression of WNT5A in idiopathic pulmonary fibrosis and its control by TGF-beta and WNT7B in human lung fibroblasts. J Histochem Cytochem 64:99–111

    CAS  Article  PubMed  Google Scholar 

  15. Vuga LJ, Ben-Yehudah A, Kovkarova-Naumovski E, Oriss T, Gibson KF, Feghali-Bostwick C, Kaminski N (2009) WNT5A is a regulator of fibroblast proliferation and resistance to apoptosis. Am J Respir Cell Mol Biol 41:583–589

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Mizutani M, Wu JC, Nusse R (2016) Fibrosis of the neonatal mouse heart after cryoinjury is accompanied by Wnt signaling activation and Epicardial-to-mesenchymal transition. J Am Heart Assoc 4:e002457

    Article  Google Scholar 

  17. Norum HM, Gullestad L, Abraityte A, Broch K, Aakhus S, Aukrust P, Ueland T (2016) Increased serum levels of the notch ligand DLL1 are associated with diastolic dysfunction, reduced exercise capacity, and adverse outcome in chronic heart failure. J Card Fail 22:218–223

    CAS  Article  PubMed  Google Scholar 

  18. Zhou Y-Y, Wang S-Q, Zhu W-Z, Chruscinski A, Kobilka BK, Ziman B, Wang S, Lakatta EG, Cheng H, Xiao R-P (2000) Culture and adenoviral infection of adult mouse cardiac myocytes: methods for cellular genetic physiology. Am J Physiol Heart Circ Physiol 279:H429–H436

    CAS  PubMed  Google Scholar 

  19. Ohm IK, Alfsnes K, Belland Olsen M, Ranheim T, Sandanger O, Dahl TB, Aukrust P, Finsen AV, Yndestad A, Vinge LE (2014) Toll-like receptor 9 mediated responses in cardiac fibroblasts. PLoS One 9:e104398

    Article  PubMed  PubMed Central  Google Scholar 

  20. Askevold ET, Aukrust P, Nymo SH, Lunde IG, Kaasboll OJ, Aakhus S, Florholmen G, Ohm IK, Strand ME, Attramadal H et al (2014) The cardiokine secreted frizzled-related protein 3, a modulator of Wnt signalling, in clinical and experimental heart failure. J Intern Med 275:621–630

    CAS  Article  PubMed  Google Scholar 

  21. Korn C, Scholz B, Hu J, Srivastava K, Wojtarowicz J, Arnsperger T, Adams RH, Boutros M, Augustin HG, Augustin I (2014) Endothelial cell-derived non-canonical Wnt ligands control vascular pruning in angiogenesis. Development 141:1757–1766

    CAS  Article  PubMed  Google Scholar 

  22. Tong L, Smyth D, Kerr C, Catterall J, Richards CD (2004) Mitogen-activated protein kinases Erk1/2 and p38 are required for maximal regulation of TIMP-1 by oncostatin M in murine fibroblasts. Cell Signal 16:1123–1132

    CAS  Article  PubMed  Google Scholar 

  23. Rauner M, Stein N, Winzer M, Goettsch C, Zwerina J, Schett G, Distler JH, Albers J, Schulze J, Schinke T et al (2012) WNT5A is induced by inflammatory mediators in bone marrow stromal cells and regulates cytokine and chemokine production. J Bone Miner Res 27:575–585

    CAS  Article  PubMed  Google Scholar 

  24. Wawrzak D, Metioui M, Willems E, Hendrickx M, de Genst E, Leyns L (2007) Wnt3a binds to several sFRPs in the nanomolar range. Biochem Biophys Res Commun 357:1119–1123

    CAS  Article  PubMed  Google Scholar 

  25. Wu D, Talbot CC, Liu Q, Jing Z-C, Damico RL, Tuder R, Barnes KC, Hassoun PM, Gao L (2016) Identifying microRNAs targeting Wnt/β-catenin pathway in end-stage idiopathic pulmonary arterial hypertension. J Mol Med 94:875–885

    CAS  Article  PubMed  Google Scholar 

  26. Boucherat O, Bonnet S (2016) MicroRNA signature of end-stage idiopathic pulmonary arterial hypertension: clinical correlations and regulation of WNT signaling. J Mol Med (Berl) 94:849–851

    Article  Google Scholar 

  27. Voelkel NF, Quaife RA, Leinwand LA, Barst RJ, McGoon MD, Meldrum DR, Dupuis J, Long CS, Rubin LJ, Smart FW et al (2006) Right ventricular function and failure: report of a National Heart, Lung, and Blood Institute working group on cellular and molecular mechanisms of right heart failure. Circulation 114:1883–1891

    Article  PubMed  Google Scholar 

  28. Shimoda LA, Laurie SS (2013) Vascular remodeling in pulmonary hypertension. J Mol Med (Berl) 91:297–309

    CAS  Article  Google Scholar 

  29. Burlew BS, Weber KT (2002) Cardiac fibrosis as a cause of diastolic dysfunction. Herz 27:92–98

    Article  PubMed  Google Scholar 

  30. Li X, Yamagata K, Nishita M, Endo M, Arfian N, Rikitake Y, Emoto N, Hirata K, Tanaka Y, Minami Y (2013) Activation of Wnt5a-Ror2 signaling associated with epithelial-to-mesenchymal transition of tubular epithelial cells during renal fibrosis. Genes Cells 18:608–619

    CAS  Article  PubMed  Google Scholar 

  31. Hartford M, Wiklund O, Mattsson Hulten L, Persson A, Karlsson T, Herlitz J, Caidahl K (2007) C-reactive protein, interleukin-6, secretory phospholipase A2 group IIA and intercellular adhesion molecule-1 in the prediction of late outcome events after acute coronary syndromes. J Intern Med 262:526–536

    CAS  Article  PubMed  Google Scholar 

  32. Fontes JA, Rose NR, Cihakova D (2015) The varying faces of IL-6: from cardiac protection to cardiac failure. Cytokine 74:62–68

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. Lindsay MM, Maxwell P, Dunn FG (2002) TIMP-1: a marker of left ventricular diastolic dysfunction and fibrosis in hypertension. Hypertension 40:136–141

    CAS  Article  PubMed  Google Scholar 

  34. Heymans S, Schroen B, Vermeersch P, Milting H, Gao F, Kassner A, Gillijns H, Herijgers P, Flameng W, Carmeliet P et al (2005) Increased cardiac expression of tissue inhibitor of metalloproteinase-1 and tissue inhibitor of metalloproteinase-2 is related to cardiac fibrosis and dysfunction in the chronic pressure-overloaded human heart. Circulation 112:1136–1144

    CAS  Article  PubMed  Google Scholar 

  35. Jordan A, Roldan V, Garcia M, Monmeneu J, de Burgos FG, Lip GY, Marin F (2007) Matrix metalloproteinase-1 and its inhibitor, TIMP-1, in systolic heart failure: relation to functional data and prognosis. J Intern Med 262:385–392

    CAS  Article  PubMed  Google Scholar 

  36. Fan D, Takawale A, Lee J, Kassiri Z (2012) Cardiac fibroblasts, fibrosis and extracellular matrix remodeling in heart disease. Fibrogenesis Tissue Repair 5:15

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. Cheng M, Wu G, Song Y, Wang L, Tu L, Zhang L, Zhang C (2016) Celastrol-induced suppression of the MiR-21/ERK Signalling pathway attenuates cardiac fibrosis and dysfunction. Cell Physiol Biochem 38:1928–1938

    CAS  Article  PubMed  Google Scholar 

  38. Nakashima A, Tamura M (2006) Regulation of matrix metalloproteinase-13 and tissue inhibitor of matrix metalloproteinase-1 gene expression by WNT3A and bone morphogenetic protein-2 in osteoblastic differentiation. Front Biosci 11:1667–1678

    CAS  Article  PubMed  Google Scholar 

  39. Ozeki N, Yamaguchi H, Hase N, Hiyama T, Kawai R, Kondo A, Nakata K, Mogi M (2015) Polyphosphate-induced matrix metalloproteinase-3-mediated proliferation in rat dental pulp fibroblast-like cells is mediated by a Wnt5 signaling cascade. Biosci Trends 9:160–168

    Article  PubMed  Google Scholar 

  40. Jung YS, Lee HY, Kim SD, Park JS, Kim JK, Suh PG, Bae YS (2013) Wnt5a stimulates chemotactic migration and chemokine production in human neutrophils. Exp Mol Med 45:e27

    Article  PubMed  Google Scholar 

  41. Katula KS, Joyner-Powell NB, Hsu CC, Kuk A (2012) Differential regulation of the mouse and human Wnt5a alternative promoters A and B. DNA Cell Biol 31:1585–1597

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. Bai C, Li X, Gao Y, Lu T, Wang K, Li Q, Xiong H, Chen J, Zhang P, Wang W et al (2014) MicroRNAs regulate the Wnt/Ca2+ signaling pathway to promote the secretion of insulin in pancreatic nestin-positive progenitor cells. bioRxiv. doi:10.1101/003913

    Google Scholar 

  43. Chen QY, Jiao DM, Zhu Y, Hu H, Wang J, Tang X, Chen J, Yan L (2016) Identification of carcinogenic potential-associated molecular mechanisms in CD133(+) A549 cells based on microRNA profiles. Tumour Biol 37:521–530

    CAS  Article  PubMed  Google Scholar 

  44. Zhang Y, Liu Z, Zhou M, Liu C (2016) MicroRNA-129-5p inhibits vascular smooth muscle cell proliferation by targeting Wnt5a. Exp Ther Med 12:2651–2656

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Meloche J, Le Guen M, Potus F, Vinck J, Ranchoux B, Johnson I, Antigny F, Tremblay E, Breuils-Bonnet S, Perros F et al (2015) miR-223 reverses experimental pulmonary arterial hypertension. Am J Physiol Cell Physiol 309:C363–C372

    CAS  Article  PubMed  Google Scholar 

  46. Tsutsui H, Kinugawa S, Matsushima S (2008) Oxidative stress and mitochondrial DNA damage in heart failure. Circ J 72 Suppl A: A31-37

  47. Potus F, Ruffenach G, Dahou A, Thebault C, Breuils-Bonnet S, Tremblay E, Nadeau V, Paradis R, Graydon C, Wong R et al (2015) Downregulation of MicroRNA-126 contributes to the failing right ventricle in pulmonary arterial hypertension. Circulation 132:932–943

    CAS  Article  PubMed  Google Scholar 

  48. Sutendra G, Dromparis P, Paulin R, Zervopoulos S, Haromy A, Nagendran J, Michelakis ED (2013) A metabolic remodeling in right ventricular hypertrophy is associated with decreased angiogenesis and a transition from a compensated to a decompensated state in pulmonary hypertension. J Mol Med (Berl) 91:1315–1327

    CAS  Article  Google Scholar 

  49. Askevold ET, Gullestad L, Nymo S, Kjekshus J, Yndestad A, Latini R, Cleland JG, McMurray JJ, Aukrust P, Ueland T (2015) Secreted frizzled related protein 3 in chronic heart failure: analysis from the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA). PLoS One 10:e0133970

    Article  PubMed  PubMed Central  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

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).

Conflict of interest

The authors declare that they have no competing interests.

Electronic supplementary material

ESM 1

(PDF 439 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-017-1529-1

Keywords

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