Wnt/β-catenin in ischemic myocardium: interactions and signaling pathways as a therapeutic target

  • Habib Haybar
  • Elahe Khodadi
  • Saeid ShahrabiEmail author


Cardiovascular disease (CVD) is still a factor of mortality in the whole world. Through canonical and noncanonical pathways and with different receptors, the Wnt/β-catenin signaling pathway plays an essential role in response to heart injuries. Wnt regulates the mobilization and proliferation of cells in endothelium and epicardium in an infarcted heart. Therefore, with its profibrotic effects as well as its antagonism with other proteins, Wnt/β-catenin signaling pathway leads to beneficial effects on fibrosis and cardiac remodeling in myocardium. In addition, Wnt increases the proliferation and differentiation of cardiac progenitors in an ischemic heart. Complex interactions and dual activity of Wnt, the changes in its expression, and mutations that can change its activity during heart development have an adverse effect on cardiac myocardium after injury. However, targeting the Wnt in myocardium with cellular and molecular pathways can be suggested to improve and repair ischemic heart. Given these challenges, in this review article, we deal with the role of Wnt/β-catenin signaling pathway as well as its interactions with other cells and molecules in an ischemic myocardium.


Wnt/β-catenin pathway Ischemia Myocardium 



We wish to thank all our colleagues in Golestan Hospital and Allied Health Sciences School, Ahvaz Jundishapur University of Medical Sciences.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human participants and/or animals

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent is not required for this type of study.


  1. 1.
    Bastakoty D, Saraswati S, Joshi P, Atkinson J, Feoktistov I, Liu J, Harris JL, Young PP (2016) Temporary, systemic inhibition of the WNT/β-catenin pathway promotes regenerative cardiac repair following myocardial infarct. Cell Stem Cells Regen Med 2(2):1–27Google Scholar
  2. 2.
    Frangogiannis NG (2008) The immune system and cardiac repair. Pharmacol Res 1;58(2):88–111Google Scholar
  3. 3.
    Deb A (2014) Cell–cell interaction in the heart via Wnt/β-catenin pathway after cardiac injury. Cardiovasc Res 102(2):214–223PubMedPubMedCentralGoogle Scholar
  4. 4.
    Haybar H, Khodadi E, Zibara K, Saki N (2018) Platelet Activation Polymorphisms in Ischemia. Cardiovasc Hematol Disord Drug Targets 18(2):153–161PubMedGoogle Scholar
  5. 5.
    Haybar H, Khodadi E, Shahjahani M, Saki N (2017) Cardiovascular events: a challenge in JAK2-positive myeloproliferative neoplasms. Cardiovasc Hematol Disord Drug Targets 17(3):161–166PubMedGoogle Scholar
  6. 6.
    Lorenzon A, Calore M, Poloni G, De Windt LJ, Braghetta P, Rampazzo A (2017) Wnt/β-catenin pathway in arrhythmogenic cardiomyopathy. Oncotarget 8(36):60640PubMedPubMedCentralGoogle Scholar
  7. 7.
    Bergmann MW (2010) WNT signaling in adult cardiac hypertrophy and remodeling: lessons learned from cardiac development. Circ Res 107(10):1198–1208PubMedGoogle Scholar
  8. 8.
    Klaus A, Saga Y, Taketo MM, Tzahor E, Birchmeier W (2007) Distinct roles of Wnt/β-catenin and Bmp signaling during early cardiogenesis. Proc Natl Acad Sci 104(47):18531–18536PubMedGoogle Scholar
  9. 9.
    Mill J, Stefanon I, Dos Santos L, Baldo M (2011) Remodeling in the ischemic heart: the stepwise progression for heart failure. Braz J Med Biol Res 44(9):890–898PubMedGoogle Scholar
  10. 10.
    Aisagbonhi O, Rai M, Ryzhov S, Atria N, Feoktistov I, Hatzopoulos AK (2011:dmm. 006510) Experimental myocardial infarction triggers canonical Wnt signaling and endothelial-to-mesenchymal transition. Dis Model Mech 4:469–483PubMedPubMedCentralGoogle Scholar
  11. 11.
    Oerlemans MI, Goumans M-J, van Middelaar B, Clevers H, Doevendans PA, Sluijter JP (2010) Active Wnt signaling in response to cardiac injury. Basic Res Cardiol 105(5):631–641PubMedPubMedCentralGoogle Scholar
  12. 12.
    Göthert JR, Gustin SE, van Eekelen JAM, Schmidt U, Hall MA, Jane SM, Green AR, Göttgens B, Izon DJ, Begley CG (2004) Genetically tagging endothelial cells in vivo: bone marrow-derived cells do not contribute to tumor endothelium. Blood 104(6):1769–1777PubMedGoogle Scholar
  13. 13.
    Melo LG, Gnecchi M, Pachori AS, Kong D, Wang K, Liu X, Pratt RE, Dzau VJ (2004) Endothelium-targeted gene and cell-based therapies for cardiovascular disease. Arterioscler Thromb Vasc Biol 24(10):1761–1774PubMedGoogle Scholar
  14. 14.
    Polakis P (2000 Aug 1) Wnt signaling and cancer. Genes Dev 14(15):1837–1851PubMedGoogle Scholar
  15. 15.
    Garcia-Gras E, Lombardi R, Giocondo MJ, Willerson JT, Schneider MD, Khoury DS, Marian AJ (2006) Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy. J Clin Invest 116:2012–2021PubMedPubMedCentralGoogle Scholar
  16. 16.
    Kim C, Wong J, Wen J, Wang S, Wang C, Spiering S, Kan NG, Forcales S, Puri PL, Leone TC, Marine JE, Calkins H, Kelly DP, Judge DP, Chen HSV (2013) Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs. Nature 494:105–110PubMedPubMedCentralGoogle Scholar
  17. 17.
    Li J, Swope D, Raess N, Cheng L, Muller EJ, Radice GL (2011) Cardiac tissue-restricted deletion of plakoglobin results in progressive cardiomyopathy and activation of {beta}-catenin signaling. Mol Cell Biol 31:1134–1144PubMedPubMedCentralGoogle Scholar
  18. 18.
    Baurand A, Zelarayan L, Betney R, Gehrke C, Dunger S, Noack C, Busjahn A, Huelsken J, Taketo MM, Birchmeier W, Dietz R, Bergmann MW (2007) β-Catenin downregulation is required for adaptive cardiac remodeling. Circ Res 100(9):1353–1362PubMedGoogle Scholar
  19. 19.
    Ueno S, Weidinger G, Osugi T, Kohn AD, Golob JL, Pabon L, Reinecke H, Moon RT, Murry CE (2007) Biphasic role for Wnt/β-catenin signaling in cardiac specification in zebrafish and embryonic stem cells. Proc Natl Acad Sci 104(23):9685–9690PubMedGoogle Scholar
  20. 20.
    Zelarayán LC, Noack C, Sekkali B, Kmecova J, Gehrke C, Renger A et al (2008) β-Catenin downregulation attenuates ischemic cardiac remodeling through enhanced resident precursor cell differentiation. Proc Natl Acad of Sci 105(50):19762–19767Google Scholar
  21. 21.
    Bowley E, O’Gorman DB, Gan BS (2007) β-Catenin signaling in fibroproliferative disease. J Surg Res 138(1):141–150PubMedGoogle Scholar
  22. 22.
    Haybar H, Shahrabi S, Zayeri ZD, Pezeshki S (2018) Strategies to increase cardioprotection through cardioprotective chemokines in chemotherapy-induced cardiotoxicity. Int J Cardiol 269:276–282Google Scholar
  23. 23.
    Gherghe CM, Duan J, Gong J, Rojas M, Klauber-Demore N, Majesky M, Deb A (2011) Wnt1 is a proangiogenic molecule, enhances human endothelial progenitor function, and increases blood flow to ischemic limbs in a HGF-dependent manner. FASEB J 25(6):1836–1843PubMedPubMedCentralGoogle Scholar
  24. 24.
    Koyanagi M, Iwasaki M, Haendeler J, Leitges M, Zeiher AM, Dimmeler S (2009) Wnt5a increases cardiac gene expressions of cultured human circulating progenitor cells via a PKC delta activation. PLoS One 4(6):e5765PubMedPubMedCentralGoogle Scholar
  25. 25.
    Limana F, Zacheo A, Mocini D, Mangoni A, Borsellino G, Diamantini A, de Mori R, Battistini L, Vigna E, Santini M, Loiaconi V, Pompilio G, Germani A, Capogrossi MC (2007) Identification of myocardial and vascular precursor cells in human and mouse epicardium. Circ Res 101(12):1255–1265PubMedGoogle Scholar
  26. 26.
    Lother A, Bergemann S, Deng L, Moser M, Bode C, Hein L (2018) Cardiac endothelial cell transcriptome. Arterioscler Thromb Vasc Biol 38:566–574PubMedGoogle Scholar
  27. 27.
    Skaria T, Bachli E, Schoedon G (2017) Wnt5A/Ryk signaling critically affects barrier function in human vascular endothelial cells. Cell Adhes Migr 11:24–38Google Scholar
  28. 28.
    Ferreira Tojais N, Peghaire C, Franzl N, Larrieu-Lahargue F, Jaspard B, Reynaud A, Moreau C, Couffinhal T, Duplaa C, Dufourcq P (2014) Frizzled7 controls vascular permeability through the Wnt-canonical pathway and cross-talk with endothelial cell junction complexes. Cardiovasc Res 103:291–303PubMedGoogle Scholar
  29. 29.
    Lie-Venema H, van den Akker N, Bax NA, Winter EM, Maas S, Kekarainen T et al (2007) Origin, fate, and function of epicardium-derived cells (EPDCs) in normal and abnormal cardiac development. Sci World J 7:1777–1798Google Scholar
  30. 30.
    Männer J, Perez-Pomares J, Macias D, Munoz-Chapuli R (2001) The origin, formation and developmental significance of the epicardium: a review. Cells Tissues Organs 169(2):89–103PubMedGoogle Scholar
  31. 31.
    Duan J, Gherghe C, Liu D, Hamlett E, Srikantha L, Rodgers L, Regan JN, Rojas M, Willis M, Leask A, Majesky M, Deb A (2012) Wnt1/βcatenin injury response activates the epicardium and cardiac fibroblasts to promote cardiac repair. EMBO J 31(2):429–442PubMedGoogle Scholar
  32. 32.
    Zhou B, Honor LB, He H, Ma Q, Oh J-H, Butterfield C, Lin RZ, Melero-Martin JM, Dolmatova E, Duffy HS, Gise A, Zhou P, Hu YW, Wang G, Zhang B, Wang L, Hall JL, Moses MA, McGowan FX, Pu WT (2011) Adult mouse epicardium modulates myocardial injury by secreting paracrine factors. J Clin Invest 121(5):1894–1904PubMedPubMedCentralGoogle Scholar
  33. 33.
    Banerjee I, Fuseler JW, Price RL, Borg TK, Baudino TA (2007) Determination of cell types and numbers during cardiac development in the neonatal and adult rat and mouse. Am J Phys Heart Circ Phys 293(3):H1883–H1H91Google Scholar
  34. 34.
    Kobayashi K, Luo M, Zhang Y, Wilkes DC, Ge G, Grieskamp T, Yamada C, Liu TC, Huang G, Basson CT, Kispert A, Greenspan DS, Sato TN (2009) Secreted frizzled-related protein 2 is a procollagen C proteinase enhancer with a role in fibrosis associated with myocardial infarction. Nat Cell Biol 11(1):46–55PubMedGoogle Scholar
  35. 35.
    Barandon L, Couffinhal T, Ezan J, Dufourcq P, Costet P, Alzieu P et al (2003) Reduction of infarct size and prevention of cardiac rupture in transgenic mice overexpressing FrzA. Circulation 108(18):2282–2289PubMedGoogle Scholar
  36. 36.
    Barandon L, Dufourcq P, Costet P, Moreau C, Allières C, Daret D et al (2005) Involvement of FrzA/sFRP-1 and the Wnt/frizzled pathway in ischemic preconditioning. Circ Res 96(12):1299–1306PubMedGoogle Scholar
  37. 37.
    Wu B, Crampton SP, Hughes CC (2007) Wnt signaling induces matrix metalloproteinase expression and regulates T cell transmigration. Immunity 26(2):227–239PubMedPubMedCentralGoogle Scholar
  38. 38.
    Egea V, Zahler S, Rieth N, Neth P, Popp T, Kehe K et al (2012) Tissue inhibitor of metalloproteinase-1 (TIMP-1) regulates mesenchymal stem cells through let-7f microRNA and Wnt/β-catenin signaling. Proc Natl Acad Sci 109(6):309–316Google Scholar
  39. 39.
    Souders CA, Bowers SL, Baudino TA (2009) Cardiac fibroblast: the renaissance cell. Circ Res 105(12):1164–1176PubMedPubMedCentralGoogle Scholar
  40. 40.
    Blankesteijn WM, van Gijn ME, Essers-Janssen YP, Daemen MJ, Smits JF (2000) β-Catenin, an inducer of uncontrolled cell proliferation and migration in malignancies, is localized in the cytoplasm of vascular endothelium during neovascularization after myocardial infarction. Am J Pathol 157(3):877–883PubMedPubMedCentralGoogle Scholar
  41. 41.
    Ezan J, Leroux L, Barandon L, Dufourcq P, Jaspard B, Moreau C, Allières C, Daret D, Couffinhal T, Duplàa C (2004) FrzA/sFRP-1, a secreted antagonist of the Wnt-frizzled pathway, controls vascular cell proliferation in vitro and in vivo. Cardiovasc Res 63(4):731–738PubMedGoogle Scholar
  42. 42.
    Lin H, Angeli M, Chung KJ, Ejimadu C, Rosa AR, Lee T (2016) sFRP2 activates Wnt/beta-catenin signaling in cardiac fibroblasts: differential roles in cell growth, energy metabolism, and extracellular matrix remodeling. Am J Physiol Cell Physiol 311:710–719Google Scholar
  43. 43.
    He W, Zhang L, Ni A, Zhang Z, Mirotsou M, Mao L, Pratt RE, Dzau VJ (2010) Exogenously administered secreted frizzled related protein 2 (Sfrp2) reduces fibrosis and improves cardiac function in a rat model of myocardial infarction. Proc Natl Acad Sci 107:21110–21115PubMedGoogle Scholar
  44. 44.
    Ye B, Ge Y, Perens G, Hong L, Xu H, Fishbein MC, Li F (2013) Canonical Wnt/β-catenin signaling in epicardial fibrosis of failed pediatric heart allografts with diastolic dysfunction. Cardiovasc Pathol 22(1):54–57PubMedGoogle Scholar
  45. 45.
    Laeremans H, Rensen SS, Ottenheijm HC, Smits JF, Blankesteijn WM (2010) Wnt/frizzled signalling modulates the migration and differentiation of immortalized cardiac fibroblasts. Cardiovasc Res 87:514–523PubMedGoogle Scholar
  46. 46.
    Paik DT, Rai M, Ryzhov S, Sanders LN, Aisagbonhi O, Funke MJ, Feoktistov I, Hatzopoulos AK (2015) Wnt10b gain-of-function improves cardiac repair by arteriole formation and attenuation of fibrosis. Circ Res 117:804–816PubMedPubMedCentralGoogle Scholar
  47. 47.
    Abraityte A, Vinge LE, Askevold ET, Lekva T, Michelsen AE, Ranheim T, Alfsnes K, Fiane A, Aakhus S, Lunde IG, Dahl CP, Aukrust P, Christensen G, Gullestad L, Yndestad A, Ueland T (2010) Wnt5a is elevated in heart failure and affects cardiac fibroblast function. J Mol Med 95:767–777Google Scholar
  48. 48.
    Qyang Y, Martin-Puig S, Chiravuri M, Chen S, Xu H, Bu L, Jiang X, Lin L, Granger A, Moretti A, Caron L, Wu X, Clarke J, Taketo MM, Laugwitz KL, Moon RT, Gruber P, Evans SM, Ding S, Chien KR (2007) The renewal and differentiation of Isl1+ cardiovascular progenitors are controlled by a Wnt/β-catenin pathway. Cell Stem Cell 1(2):165–179PubMedGoogle Scholar
  49. 49.
    Bondue A, Lapouge G, Paulissen C, Semeraro C, Iacovino M, Kyba M, Blanpain C (2008) Mesp1 acts as a master regulator of multipotent cardiovascular progenitor specification. Cell Stem Cell 3(1):69–84PubMedGoogle Scholar
  50. 50.
    Lindsley RC, Gill JG, Murphy TL, Langer EM, Cai M, Mashayekhi M, Wang W, Niwa N, Nerbonne JM, Kyba M, Murphy KM (2008) Mesp1 coordinately regulates cardiovascular fate restriction and epithelial-mesenchymal transition in differentiating ESCs. Cell Stem Cell 3(1):55–68PubMedPubMedCentralGoogle Scholar
  51. 51.
    David R, Brenner C, Stieber J, Schwarz F, Brunner S, Vollmer M, Mentele E, Müller-Höcker J, Kitajima S, Lickert H, Rupp R, Franz WM (2008) MesP1 drives vertebrate cardiovascular differentiation through Dkk-1-mediated blockade of Wnt-signalling. Nat Cell Biol 10(3):338–345PubMedGoogle Scholar
  52. 52.
    Naito AT, Shiojima I, Akazawa H, Hidaka K, Morisaki T, Kikuchi A, Komuro I (2006) Developmental stage-specific biphasic roles of Wnt/β-catenin signaling in cardiomyogenesis and hematopoiesis. Proc Natl Acad Sci 103(52):19812–19817PubMedGoogle Scholar
  53. 53.
    Zhu W, Shiojima I, Ito Y, Li Z, Ikeda H, Yoshida M, Naito AT, Nishi JI, Ueno H, Umezawa A, Minamino T, Nagai T, Kikuchi A, Asashima M, Komuro I (2008) IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis. Nature 454(7202):345–349PubMedGoogle Scholar
  54. 54.
    Olson EN (2001) The path to the heart and the road not taken. Science 291(5512):2327–2328PubMedGoogle Scholar
  55. 55.
    Rao TP, Kühl M (2010) An updated overview on Wnt signaling pathways: a prelude for more. Circ Res 106(12):1798–1806PubMedGoogle Scholar
  56. 56.
    Buikema JW, Mady AS, Mittal NV, Atmanli A, Caron L, Doevendans PA et al (2013) Wnt/β-catenin signaling directs the regional expansion of first and second heart field-derived ventricular cardiomyocytes. Development 140(20):1–12Google Scholar
  57. 57.
    Brault V, Moore R, Kutsch S, Ishibashi M, Rowitch DH, McMahon AP, Sommer L, Boussadia O, Kemler R (2001) Inactivation of the (β)-catenin gene by Wnt1-Cre-mediated deletion results in dramatic brain malformation and failure of craniofacial development. Development 128(8):1253–1264PubMedPubMedCentralGoogle Scholar
  58. 58.
    Gessert S, Kühl M (2010) The multiple phases and faces of Wnt signaling during cardiac differentiation and development. Circ Res 107(2):186–199PubMedGoogle Scholar
  59. 59.
    Wesley CS (1999) Notch and wingless regulate expression of cuticle patterning genes. Mol Cell Biol 19(8):5743–5758PubMedPubMedCentralGoogle Scholar
  60. 60.
    Schumann H, Holtz J, Zerkowski H-R, Hatzfeld M (2000) Expression of secreted frizzled related proteins 3 and 4 in human ventricular myocardium correlates with apoptosis related gene expression. Cardiovasc Res 45(3):720–728PubMedGoogle Scholar
  61. 61.
    Ter Horst P, Smits J, Blankesteijn W (2012) The Wnt/frizzled pathway as a therapeutic target for cardiac hypertrophy: where do we stand? Acta Physiol 204(1):110–117Google Scholar
  62. 62.
    Maretto S, Cordenonsi M, Dupont S, Braghetta P, Broccoli V, Hassan AB, Volpin D, Bressan GM, Piccolo S (2003) Mapping Wnt/β-catenin signaling during mouse development and in colorectal tumors. Proc Natl Acad Sci 100(6):3299–3304PubMedGoogle Scholar
  63. 63.
    Daskalopoulos EP, Hermans KC, Janssen BJ, Blankesteijn WM (2013) Targeting the Wnt/frizzled signaling pathway after myocardial infarction: a new tool in the therapeutic toolbox? Trends Cardiovasc Med 23(4):121–127PubMedGoogle Scholar
  64. 64.
    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(6):1409–1432PubMedGoogle Scholar
  65. 65.
    Tao H, Yang J-J, Shi K-H, Li J (2016) Wnt signaling pathway in cardiac fibrosis: new insights and directions. Metabolism 65(2):30–40PubMedGoogle Scholar
  66. 66.
    Chen L, Zhuang J, Singh S, Wang K, Xiong M, Xu D, Chen W, Pang J, Xu Y, Li X (2016) XAV939 inhibits intima formation by decreasing vascular smooth muscle cell proliferation and migration through blocking Wnt signaling. J Cardiovasc Pharmacol 68(6):414–424PubMedGoogle Scholar
  67. 67.
    Gay A, Towler DA (2017) Wnt signaling in cardiovascular disease: opportunities and challenges. Curr Opin Lipidol 28(5):387–396PubMedPubMedCentralGoogle Scholar
  68. 68.
    Kawano Y, Kypta R (2003) Secreted antagonists of the Wnt signalling pathway. J Cell Sci 116(13):2627–2634PubMedGoogle Scholar
  69. 69.
    Domian IJ, Chiravuri M, Van Der Meer P, Feinberg AW, Shi X, Shao Y et al (2009) Generation of functional ventricular heart muscle from mouse ventricular progenitor cells. Science 326(5951):426–429PubMedPubMedCentralGoogle Scholar
  70. 70.
    Barcelos LS, Duplaa C, Kränkel N, Graiani G, Invernici G, Katare R et al (2009) Human CD133+ progenitor cells promote the healing of diabetic ischemic ulcers by paracrine stimulation of angiogenesis and activation of Wnt signaling. Circ Res 104(9):1095–1102PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Atherosclerosis Research CenterAhvaz Jundishapur University of Medical SciencesAhvazIran
  2. 2.Research Center of Thalassemia and Hemoglobinopathy, Health research instituteAhvaz Jundishapur University of Medical SciencesAhvazIran
  3. 3.Department of biochemistry and hematology, faculty of medicineSemnan University of Medical SciencesSemnanIran

Personalised recommendations