CoChat
Sign Up
Cited by 64Cardiovascular Effects of ExerciseCardiomyopathy and Myosin StudiesCardiac electrophysiology and arrhythmias

Wnt/β-catenin pathway in arrhythmogenic cardiomyopathy

Open access
Lorenzon, Alessandra, Calore, Martina, Poloni, Giulia, De Windt, Leon J., Braghetta, Paola, Rampazzo, Alessandra·2017·Oncotarget
DOI 10.18632/oncotarget.17457PMC PMC5601168
Open this paper in CoChat — free accountOpen PDF

Abstract

// Alessandra Lorenzon 1 , Martina Calore 2 , Giulia Poloni 1 , Leon J. De Windt 2 , Paola Braghetta 3 and Alessandra Rampazzo 1 1 University of Padua, Department of Biology, Padua, Italy 2 Maastricht University, Department of Cardiology, Maastricht, The Netherlands 3 University of Padua, Department of Molecular Medicine, Padua, Italy Correspondence to: Alessandra Rampazzo, email: alessandra.rampazzo@unipd.it Keywords: Wnt, β-catenin, microRNAs, arrhythmogenic cardiomyopathy, molecular pathogenesis Received: January 30, 2017 Accepted: April 14, 2017 Published: April 27, 2017 ABSTRACT Wnt/β-catenin signaling pathway plays essential roles in heart development as well as cardiac tissue homoeostasis in adults. Abnormal regulation of this signaling pathway is linked to a variety of cardiac disease conditions, including hypertrophy, fibrosis, arrhythmias, and infarction. Recent studies on genetically modified cellular and animal models document a crucial role of Wnt/β-catenin signaling in the molecular pathogenesis of arrhythmogenic cardiomyopathy (AC), an inherited disease of intercalated discs, typically characterized by ventricular arrhythmias and progressive substitution of the myocardium with fibrofatty tissue. In this review, we summarize the conflicting published data regarding the Wnt/β-catenin signaling contribution to AC pathogenesis and we report the identification of a new potential therapeutic molecule that prevents myocyte injury and cardiac dysfunction due to desmosome mutations in vitro and in vivo by interfering in this signaling pathway. Finally, we underline the potential function of microRNAs, epigenetic regulatory RNA factors reported to participate in several pathological responses in heart tissue and in the Wnt signaling network, as important modulators of Wnt/β-catenin signaling transduction in AC. Elucidation of the precise regulatory mechanism of Wnt/β-catenin signaling in AC molecular pathogenesis could provide fundamental insights for new mechanism-based therapeutic strategy to delay the onset or progression of this cardiac disease.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.18632/oncotarget.17457

Cites

6 of 6 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Suppression of canonical Wnt/β-catenin signaling leads to ACM, prominently through competition with nuclear localization of JUP, rather than through β-catenin degradation.

    “In a landmark study by Garcia-Gras E et al. [77], these authors demonstrated that suppression of canonical Wnt/β-catenin signaling leads to ACM, prominently through competition with nuclear localization of JUP, rather than through β-catenin degradation [77,79,80].”

    From A Paradigm Shift: Arrhythmogenic Cardiomyopathy Is an Inflammatory Disease (2026) · cites this paper as [80]

    In 'Wnt signaling in AC: conflicting evidences' (page unavailable), the review reports that nuclear translocation of JUP/plakoglobin suppresses Wnt/β-catenin signaling and interferes with β-catenin/Tcf activity. It does not establish that this mechanism predominates over β-catenin degradation; the same section describes other, conflicting mechanisms in AC. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Loss of nuclear YAP in conjunction with Wnt/β-catenin suppression further drives adipogenesis and maladaptive fibrotic repair.

    “The loss of nuclear YAP in conjunction with Wnt/β-catenin suppression further drives adipogenesis and maladaptive fibrotic repair [79,80].”

    From A Paradigm Shift: Arrhythmogenic Cardiomyopathy Is an Inflammatory Disease (2026) · cites this paper as [80]

    The Introduction’s “Wnt signaling in AC: conflicting evidences” section links cytoplasmic retention of YAP and suppression of Wnt/β-catenin activity to enhanced heart adipogenesis. It does not link that combined mechanism to maladaptive fibrotic repair; the separate “cardiac disease and repair” section instead discusses fibrogenesis in connection with Wnt activation. Page numbers are unavailable in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 125

  1. [1]Gessert S Kühl M The multiple phases and faces of wnt signaling during cardiac differentiation and development Circ Res 2010 107 186 99 20651295
  2. [2]Clevers H Nusse R Wnt/β-catenin signaling and disease Cell 2012 149 1192 205 22682243
  3. [3]Moon RT Kohn AD De Ferrari GV Kaykas A WNT and beta-catenin signalling: diseases and therapies Nat Rev Genet 2004 5 691 701 15372092
  4. [4]Clevers H Wnt/beta-catenin signaling in development and disease Cell 2006 127 469 80 17081971
  5. [5]Nusse R Varmus HE Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome Cell 1982 31 99 109 6297757
  6. [6]Kinzler KW Nilbert MC Su LK Vogelstein B Bryan TM Levy DB Smith KJ Preisinger AC Hedge P McKechnie D Finniear R Markham A Groffen J Identification of FAP locus genes from chromosome 5q21 Science 1991 253 661 65 1651562
  7. [7]Nishisho I Nakamura Y Miyoshi Y Miki Y Ando H Horii A Koyama K Utsunomiya J Baba S Hedge P Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients Science 1991 253 665 69 1651563
  8. [8]Neben CL Merrill AE Signaling pathways in craniofacial development: insights from rare skeletal disorders Curr Top Dev Biol 2015 115 493 542 26589936
  9. [9]Libro R Bramanti P Mazzon E The role of the Wnt canonical signaling in neurodegenerative diseases Life Sci 2016 158 78 88 27370940
  10. [10]Alfaro MP Pagni M Vincent A Atkinson J Hill MF Cates J Davidson JM Rottman J Lee E Young PP The Wnt modulator sFRP2 enhances mesenchymal stem cell engraftment, granulation tissue formation and myocardial repair Proc Natl Acad Sci USA 2008 105 18366 71 19017790 PMC2587631
  11. [11]van de Schans VA Smits JF Blankesteijn WM The Wnt/frizzled pathway in cardiovascular development and disease: friend or foe? Eur J Pharmacol 2008 585 338 45 18417121
  12. [12]Dawson K Aflaki M Nattel S Role of the Wnt-Frizzled system in cardiac pathophysiology: a rapidly developing, poorly understood area with enormous potential J Physiol 2013 591 1409 32 23207593 PMC3607163
  13. [13]Pahnke A Conant G Huyer LD Zhao Y Feric N Radisic M The role of Wnt regulation in heart development, cardiac repair and disease: A tissue engineering perspective Biochem Biophys Res Commun 2016 473 698 703 26626076 PMC4854783
  14. [14]Garcia-Gras E Lombardi R Giocondo MJ Willerson JT Schneider MD Khoury DS Marian AJ Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy J Clin Invest 2006 116 2012 21 16823493 PMC1483165
  15. [15]Calore M Lorenzon A De Bortoli M Poloni G Rampazzo A Arrhythmogenic cardiomyopathy: a disease of intercalated discs Cell Tissue Res 2015 360 491 500 25344329
  16. [16]Miller JR The Wnts Genome Biol 2002 3 REVIEWS3001 11806834 PMC150458
  17. [17]Yang Y Wnts and wing: wnt signaling in vertebrate limb development and musculoskeletal morphogenesis Birth Defects Res C Embryo Today 2003 69 305 17 14745971
  18. [18]Nusse R van Ooyen A Cox D Fung YK Varmus H Mode of proviral activation of a putative mammary oncogene (int-1) on mouse chromosome 15 Nature 1984 307 131 36 6318122
  19. [19]Rijsewijk F Schuermann M Wagenaar E Parren P Weigel D Nusse R The Drosophila homolog of the mouse mammary oncogene int-1 is identical to the segment polarity gene wingless Cell 1987 50 649 57 3111720
  20. [20]Kawano Y Kypta R Secreted antagonists of the Wnt signalling pathway J Cell Sci 2003 116 2627 34 12775774
  21. [21]Gao C Chen YG Dishevelled: the hub of Wnt signaling Cell Signal 2010 22 717 27 20006983
  22. [22]Kikuchi A Yamamoto H Sato A Matsumoto S New insights into the mechanism of Wnt signaling pathway activation Int Rev Cell Mol Biol 2011 291 21 71 22017973
  23. [23]Mikels AJ Nusse R Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context PLoS Biol 2006 4 e115 16602827 PMC1420652
  24. [24]Umbhauer M Djiane A Goisset C Penzo-Méndez A Riou JF Boucaut JC Shi DL The C-terminal cytoplasmic Lys-thr-X-X-X-Trp motif in frizzled receptors mediates Wnt/β-catenin signalling EMBO J 2000 19 4944 54 10990458 PMC314225
  25. [25]Dann CE Hsieh JC Rattner A Sharma D Nathans J Leahy DJ Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains Nature 2001 412 86 90 11452312
  26. [27]Acebron SP Niehrs C β-Catenin-independent roles of Wnt/LRP6 signaling Trends Cell Biol 2016 26 956 67 27568239
  27. [28]Aktary Z Bertrand JU Larue L The WNT-less wonder: WNT-independent β-catenin signaling Pigment Cell Melanoma Res 2016 29 524 40 27311806
  28. [29]Lam AP Gottardi CJ β-catenin signaling: a novel mediator of fibrosis and potential therapeutic target Curr Opin Rheumatol 2011 23 562 67 21885974 PMC3280691
  29. [30]He X Semenov M Tamai K Zeng X LDL receptor-related proteins 5 and 6 in Wnt/β-catenin signaling: arrows point the way Development 2004 131 1663 77 15084453
  30. [31]Komiya Y Habas R Wnt signal transduction pathways Organogenesis 2008 4 68 75 19279717 PMC2634250
  31. [32]Ben-Ze'ev A Shtutman M Zhurinsky J The integration of cell adhesion with gene expression: the role of beta-catenin Exp Cell Res 2000 261 75 82 11082277
  32. [33]Giles RH van Es JH Clevers H Caught up in a Wnt storm: wnt signaling in cancer Biochim Biophys Acta 2003 1653 1 24 12781368
  33. [34]Rao TP Kühl M An updated overview on Wnt signaling pathways: a prelude for more Circ Res 2010 106 1798 806 20576942
  34. [35]Hrckulak D Kolar M Strnad H Korinek V TCF/LEF transcription factors: an update from the internet resources Cancers (Basel) 2016 8 E70 27447672 PMC4963812
  35. [36]Wong HC Bourdelas A Krauss A Lee HJ Shao Y Wu D Mlodzik M Shi DL Zheng J Direct binding of the PDZ domain of Dishevelled to a conserved internal sequence in the C-terminal region of Frizzled Mol Cell 2003 12 1251 60 14636582 PMC4381837
  36. [38]Lickert H Kutsch S Kanzler B Tamai Y Taketo MM Kemler R Formation of multiple hearts in mice following deletion of beta-catenin in the embryonic endoderm Dev Cell 2002 3 171 81 12194849
  37. [39]Tzahor E Wnt/beta-catenin signaling and cardiogenesis: timing does matter Dev Cell 2007 13 10 13 17609106
  38. [40]Ruiz-Villalba A Hoppler S van den Hoff MJ Wnt signaling in the heart fields: variations on a common theme Dev Dyn 2016 245 294 306 26638115
  39. [41]Haegel H Larue L Ohsugi M Fedorov L Herrenknecht K Kemler R Lack of beta-catenin affects mouse development at gastrulation Development 1995 121 3529 37 8582267
  40. [42]Ueno S Weidinger G Osugi T Kohn AD Golob JL Pabon L Reinecke H Moon RT Murry CE Biphasic role for Wnt/beta-catenin signaling in cardiac specification in zebrafish and embryonic stem cells Proc Natl Acad Sci USA 2007 104 9685 90 17522258 PMC1876428
  41. [43]Klaus A Saga Y Taketo MM Tzahor E Birchmeier W Distinct roles of Wnt/beta-catenin and Bmp signaling during early cardiogenesis Proc Natl Acad Sci USA 2007 104 18531 36 18000065 PMC2141811
  42. [44]Paige SL Osugi T Afanasiev OK Pabon L Reinecke H Murry CE Endogenous Wnt/beta-catenin signaling is required for cardiac differentiation in human embryonic stem cells PLoS One 2010 5 e11134 20559569 PMC2886114
  43. [45]van Gijn ME Blankesteijn WM Smits JF Hierck B Gittenberger-de Groot AC Frizzled 2 is transiently expressed in neural crest-containing areas during development of the heart and great arteries in the mouse Anat Embryol (Berl) 2001 203 185 92 11303904
  44. [46]Liebner S Cattelino A Gallini R Rudini N Iurlaro M Piccolo S Dejana E Beta-catenin is required for endothelial-mesenchymal transformation during heart cushion development in the mouse J Cell Biol 2004 166 359 67 15289495 PMC2172268
  45. [47]Afouda BA Martin J Liu F Ciau-Uitz A Patient R Hoppler S GATA transcription factors integrate Wnt signalling during heart development Development 2008 135 3185 90 18715946
  46. [48]Afouda BA Hoppler S Different requirements for GATA factors in cardiogenesis are mediated by non-canonical Wnt signaling Dev Dyn 2011 240 649 62 21305652
  47. [49]Duan J Gherghe C Liu D Hamlett E Srikantha L Rodgers L Regan JN Rojas M Willis M Leask A Majesky M Deb A Wnt1/βcatenin injury response activates the epicardium and cardiac fibroblasts to promote cardiac repair EMBO J 2012 31 429 42 22085926 PMC3261567
  48. [50]Ponnusamy M Li PF Wang K Understanding cardiomyocyte proliferation: an insight into cell cycle activity Cell Mol Life Sci 2016 PMC11107761 27695872
  49. [51]Tseng AS Engel FB Keating MT The GSK-3 inhibitor BIO promotes proliferation in mammalian cardiomyocytes Chem Biol 2006 13 957 63 16984885
  50. [52]Heallen T Zhang M Wang J Bonilla-Claudio M Klysik E Johnson RL Martin JF Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size Science 2011 332 458 61 21512031 PMC3133743
  51. [53]Maretto S Cordenonsi M Dupont S Braghetta P Broccoli V Hassan AB Volpin D Bressan GM Piccolo S Mapping Wnt/beta-catenin signaling during mouse development and in colorectal tumors Proc Natl Acad Sci USA 2003 100 3299 304 12626757 PMC152286
  52. [54]ter Horst P Smits JF Blankesteijn WM The Wnt/Frizzled pathway as a therapeutic target for cardiac hypertrophy: where do we stand? Acta Physiol (Oxf) 2012 204 110 17 21624093
  53. [55]Tarone G Lembo G Molecular interplay between mechanical and humoral signalling in cardiac hypertrophy Trends Mol Med 2003 9 376 82 13129703
  54. [56]Malekar P Hagenmueller M Anyanwu A Buss S Streit MR Weiss CS Wolf D Riffel J Bauer A Katus HA Hardt SE Wnt signaling is critical for maladaptive cardiac hypertrophy and accelerates myocardial remodeling Hypertension 2010 55 939 45 20177000
  55. [57]Hunter JJ Chien KR Signaling pathways for cardiac hypertrophy and failure N Engl J Med 1999 341 1276 83 10528039
  56. [58]Michael A Haq S Chen X Hsich E Cui L Walters B Shao Z Bhattacharya K Kilter H Huggins G Andreucci M Periasamy M Solomon RN Glycogen synthase kinase-3beta regulates growth, calcium homeostasis, and diastolic function in the heart J Biol Chem 2004 279 21383 93 15020584
  57. [59]Chen X Shevtsov SP Hsich E Cui L Haq S Aronovitz M Kerkelä R Molkentin JD Liao R Salomon RN Patten R Force T The beta-catenin/T-cell factor/lymphocyte enhancer factor signaling pathway is required for normal and stress-induced cardiac hypertrophy Mol Cell Biol 2006 26 4462 73 16738313 PMC1489123
  58. [60]van de Schans VA van den Borne SW Strzelecka AE Janssen BJ van der Velden JL Langen RC Wynshaw-Boris A Smits JF Blankesteijn WM Interruption of Wnt signaling attenuates the onset of pressure overload-induced cardiac hypertrophy Hypertension 2007 49 473 80 17210832
  59. [61]Tateishi A Matsushita M Asai T Masuda Z Kuriyama M Kanki K Ishino K Kawada M Sano S Matsui H Effect of inhibition of glycogen synthase kinase-3 on cardiac hypertrophy during acute pressure overload Gen Thorac Cardiovasc Surg 2010 58 265 70 20549454
  60. [62]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 Secreted Frizzled-related protein 2 is a procollagen C proteinase enhancer with a role in fibrosis associated with myocardial infarction Nat Cell Biol 2009 11 46 55 19079247 PMC2722759
  61. [63]Ye B Ge Y Perens G Hong L Xu H Fishbein MC Li F Canonical Wnt/β-catenin signaling in epicardial fibrosis of failed pediatric heart allografts with diastolic dysfunction Cardiovasc Pathol 2013 22 54 57 22475572 PMC3427707
  62. [64]Benito B Gay-Jordi G Serrano-Mollar A Guasch E Shi Y Tardif JC Brugada J Nattel S Mont L Cardiac arrhythmogenic remodeling in a rat model of long-term intensive exercise training Circulation 2011 123 13 22 21173356
  63. [65]Rohr S Arrhythmogenic implications of fibroblast-myocyte interactions Circ Arrhythm Electrophysiol 2012 5 442 52 22511661
  64. [66]Hamburg EJ Atit RP Sustained β-catenin activity in dermal fibroblasts is sufficient for skin fibrosis J Invest Dermatol 2012 132 2469 72 22622416 PMC3430808
  65. [68]Haq S Choukroun G Lim H Tymitz KM del Monte F Gwathmey J Grazette L Michael A Hajjar R Force T Molkentin JD Differential activation of signal transduction pathways in human hearts with hypertrophy versus advanced heart failure Circulation 2001 103 670 77 11156878
  66. [69]Ai Z Fischer A Spray DC Brown AM Fishman GI Wnt-1 regulation of connexin43 in cardiac myocytes J Clin Invest 2000 105 161 71 10642594 PMC377428
  67. [70]Thiene G Nava A Corrado D Rossi L Pennelli N Right ventricular cardiomyopathy and sudden death in young people N Engl J Med 1988 318 129 33 3336399
  68. [71]Nava A Thiene G Canciani B Scognamiglio R Daliento L Buja G Martini B Stritoni P Fasoli G Familial occurrence of right ventricular dysplasia: a study involving nine families J Am Coll Cardiol 1988 12 1222 28 3170963
  69. [72]Basso C Corrado D Thiene G Cardiovascular causes of sudden death in young individuals including athletes Cardiol Rev 1999 7 127 35 10423663
  70. [73]Tabib A Loire R Chalabreysse L Meyronnet D Miras A Malicier D Thivolet F Chevalier P Bouvagnet P Circumstances of death and gross and microscopic observations in a series of 200 cases of sudden death associated with arrhythmogenic right ventricular cardiomyopathy and/or dysplasia Circulation 2003 108 3000 05 14662701
  71. [74]Corrado D Basso C Thiene G McKenna WJ Davies MJ Fontaliran F Nava A Silvestri F Blomström-Lundqvist C Wlodarska EK Fontaine G Camerini F Spectrum of clinicopathologic manifestations of arrhythmogenic right ventricular cardiomyopathy/dysplasia: a multicenter study J Am Coll Cardiol 1997 30 1512 20 9362410
  72. [75]Basso C Bauce B Corrado D Thiene G Pathophysiology of arrhythmogenic cardiomyopathy Nat Rev Cardiol 2011 9 223 33 22124316
  73. [76]Te Riele AS James CA Philips B Rastegar N Bhonsale A Groeneweg JA Murray B Tichnell C Judge DP Van Der Heijden JF Cramer MJ Velthuis BK Bluemke DA Mutation-positive arrhythmogenic right ventricular dysplasia/cardiomyopathy: the triangle of dysplasia displaced J Cardiovasc Electrophysiol 2013 24 1311 20 23889974 PMC3971054
  74. [77]McKenna WJ Thiene G Nava A Fontaliran F Blomström-Lundqvist C Fontaine G Camerini F Task Force of the Working Group Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy Br Heart J 1994 71 215 18 8142187 PMC483655
  75. [78]Marcus FI McKenna WJ Sherrill D Basso C Bauce B Bluemke DA Calkins H Corrado D Cox MG Daubert JP Fontaine G Gear K Hauer R Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria Circulation 2010 121 1533 41 20172911 PMC2860804
  76. [79]Rampazzo A Nava A Danieli GA Buja G Daliento L Fasoli G Scognamiglio R Corrado D Thiene G The gene for arrhythmogenic right ventricular cardiomyopathy maps to chromosome 14q23-q24 Hum Mol Genet 1994 3 959 62 7951245
  77. [80]Poloni G De Bortoli M Calore M Rampazzo A Lorenzon A Arrhythmogenic right-ventricular cardiomyopathy: molecular genetics into clinical practice in the era of next generation sequencing J Cardiovasc Med (Hagerstown) 2016 17 399 407 26990921
  78. [81]Groeneweg JA Bhonsale A James CA te Riele AS Dooijes D Tichnell C Murray B Wiesfeld AC Sawant AC Kassamali B Atsma DE Volders PG de Groot NM Clinical Presentation, Long-Term Follow-Up, and Outcomes of 1001 Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Patients and Family Members Circ Cardiovasc Genet 2015 8 437 46 25820315
  79. [82]Rampazzo A Nava A Malacrida S Beffagna G Bauce B Rossi V Zimbello R Simionati B Basso C Thiene G Towbin JA Danieli GA Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy Am J Hum Genet 2002 71 1200 06 12373648 PMC385098
  80. [83]Gerull B Heuser A Wichter T Paul M Basson CT McDermott DA Lerman BB Markowitz SM Ellinor PT MacRae CA Peters S Grossmann KS Drenckhahn J Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy Nat Genet 2004 36 1162 64 15489853
  81. [84]Pilichou K Nava A Basso C Beffagna G Bauce B Lorenzon A Frigo G Vettori A Valente M Towbin J Thiene G Danieli GA Rampazzo A Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy Circulation 2006 113 1171 79 16505173
  82. [85]Syrris P Ward D Evans A Asimaki A Gandjbakhch E Sen-Chowdhry S McKenna WJ Arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in the desmosomal gene desmocollin-2 Am J Hum Genet 2006 79 978 84 17033975 PMC1698574
  83. [86]Asimaki A Syrris P Wichter T Matthias P Saffitz JE McKenna WJ A novel dominant mutation in plakoglobin causes arrhythmogenic right ventricular cardiomyopathy Am J Hum Genet 2007 81 964 73 17924338 PMC2265660
  84. [87]van Hengel J Calore M Bauce B Dazzo E Mazzotti E De Bortoli M Lorenzon A Li Mura IE Beffagna G Rigato I Vleeschouwers M Tyberghein K Hulpiau P Mutations in the area composita protein αT-catenin are associated with arrhythmogenic right ventricular cardiomyopathy Eur Heart J 2013 34 201 10 23136403
  85. [88]Franke WW Borrmann CM Grund C Pieperhoff S The area composita of adhering junctions connecting heart muscle cells of vertebrates. I. Molecular definition in intercalated disks of cardiomyocytes by immunoelectron microscopy of desmosomal proteins Eur J Cell Biol 2006 85 69 82 16406610
  86. [89]Sato PY Coombs W Lin X Nekrasova O Green KJ Isom LL Taffet SM Delmar M Interactions between ankyrin-G, Plakophilin-2, and Connexin43 at the cardiac intercalated disc Circ Res 2011 109 193 201 21617128 PMC3139453
  87. [90]Ross SE Hemati N Longo KA Bennett CN Lucas PC Erickson RL MacDougald OA Inhibition of adipogenesis by Wnt signaling Science 2000 289 950 53 10937998
  88. [91]Lombardi R Dong J Rodriguez G Bell A Leung TK Schwartz RJ Willerson JT Brugada R Marian AJ Genetic fate mapping identifies second heart field progenitor cells as a source of adipocytes in arrhythmogenic right ventricular cardiomyopathy Circ Res 2009 104 1076 84 19359597 PMC2767296
  89. [92]Lombardi R da Graca Cabreira-Hansen M Bell A Fromm RR Willerson JT Marian AJ Nuclear plakoglobin is essential for differentiation of cardiac progenitor cells to adipocytes in arrhythmogenic right ventricular cardiomyopathy Circ Res 2011 109 1342 53 22021931 PMC3237769
  90. [94]Lombardi R Chen SN Ruggiero A Gurha P Czernuszewicz GZ Willerson JT Marian AJ Cardiac fibro-adipocyte progenitors express desmosome proteins and preferentially differentiate to adipocytes upon deletion of the desmoplakin gene Circ Res 2016 119 41 54 27121621 PMC4920717
  91. [95]Martherus R Jain R Takagi K Mendsaikhan U Turdi S Osinska H James JF Kramer K Purevjav E Towbin JA Accelerated cardiac remodeling in desmoplakin transgenic mice in response to endurance exercise is associated with perturbed Wnt/β-catenin signaling Am J Physiol Heart Circ Physiol 2016 310 H174 87 26545710 PMC4796627
  92. [96]Asimaki A Kapoor S Plovie E Karin Arndt A Adams E Liu Z James CA Judge DP Calkins H Churko J Wu JC MacRae CA Kléber AG Saffitz JE Identification of a new modulator of the intercalated disc in a zebrafish model of arrhythmogenic cardiomyopathy Sci Transl Med 2014 6 240ra74 PMC4471875 24920660
  93. [98]Li J Swope D Raess N Cheng L Muller EJ Radice GL Cardiac tissue-restricted deletion of plakoglobin results in progressive cardiomyopathy and activation of {beta}-catenin signaling Mol Cell Biol 2011 31 1134 44 21245375 PMC3067899
  94. [99]Li D Liu Y Maruyama M Zhu W Chen H Zhang W Reuter S Lin SF Haneline LS Field LJ Chen PS Shou W Restrictive loss of plakoglobin in cardiomyocytes leads to arrhythmogenic cardiomyopathy Hum Mol Genet 2011 20 4582 96 21880664 PMC3209829
  95. [100]Oxford EM Danko CG Fox PR Kornreich BG Moïse NS Change in β-catenin localization suggests involvement of the canonical Wnt pathway in Boxer dogs with arrhythmogenic right ventricular cardiomyopathy J Vet Intern Med 2014 28 92 101 24428316 PMC4895526
  96. [101]Ma D Wei H Lu J Ho S Zhang G Sun X Oh Y Tan SH Ng ML Shim W Wong P Liew R Generation of patient-specific induced pluripotent stem cell-derived cardiomyocytes as a cellular model of arrhythmogenic right ventricular cardiomyopathy Eur Heart J 2013 34 1122 33 22798562
  97. [102]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 Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs Nature 2013 494 105 10 23354045 PMC3753229
  98. [104]Wen JY Wei CY Shah K Wong J Wang C Chen HS Maturation-based model of arrhythmogenic right ventricular dysplasia using patient-specific induced pluripotent stem cells Circ J 2015 79 1402 08 25971409
  99. [105]Lu B Green BA Farr JM Lopes FC Van Raay TJ Wnt drug discovery: weaving through the screens, patents and clinical trials Cancers (Basel) 2016 8 E82 27598201 PMC5040984
  100. [106]Eldar-Finkelman H Martinez A GSK-3 inhibitors: preclinical and clinical focus on CNS Front Mol Neurosci 2011 4 32 22065134 PMC3204427
  101. [107]Ambros V The functions of animal microRNAs Nature 2004 431 350 55 15372042
  102. [108]Leptidis S El Azzouzi H Lok SI de Weger R Olieslagers S Kisters N Silva GJ Heymans S Cuppen E Berezikov E De Windt LJ da Costa Martins P A deep sequencing approach to uncover the miRNOME in the human heart PLoS One 2013 8 e57800 23460909 PMC3583901
  103. [109]Zhang LL Liu JJ Liu F Liu WH Wang YS Zhu B Yu B MiR-499 induces cardiac differentiation of rat mesenchymal stem cells through wnt/β-catenin signaling pathway Biochem Biophys Res Commun 2012 420 875 81 22465011
  104. [110]Lu TY Lin B Li Y Arora A Han L Cui C Coronnello C Sheng Y Benos PV Yang L Overexpression of microRNA-1 promotes cardiomyocyte commitment from human cardiovascular progenitors via suppressing WNT and FGF signaling pathways J Mol Cell Cardiol 2013 63 146 54 23939491 PMC4268488
  105. [111]Li M Hu X Zhu J Zhu C Zhu S Liu X Xu J Han S Yu Z Overexpression of miR-19b impairs cardiac development in zebrafish by targeting ctnnb1 Cell Physiol Biochem 2014 33 1988 2002 25034767
  106. [112]Qin DN Qian L Hu DL Yu ZB Han SP Zhu C Wang X Hu X Effects of miR-19b overexpression on proliferation, differentiation, apoptosis and Wnt/β-catenin signaling pathway in P19 cell model of cardiac differentiation in vitro Cell Biochem Biophys 2013 66 709 22 23443808
  107. [113]Liu X Yang L Wang H Xu G Zhu S Li M Hu X Zhu J Zhu C Xu J Han S Yu Z Effects of miR-19b knockdown on the cardiac differentiation of P19 mouse embryonic carcinoma cells Mol Med Rep 2015 11 2504 12 25483911 PMC4337596
  108. [114]Mayorga ME Penn MS miR-145 is differentially regulated by TGF-β1 and ischaemia and targets Disabled-2 expression and wnt/β-catenin activity J Cell Mol Med 2012 16 1106 13 21762377 PMC4365889
  109. [115]Zhang H Liu S Dong T Yang J Xie Y Wu Y Kang K Hu S Gou D Wei Y Profiling of differentially expressed microRNAs in arrhythmogenic right ventricular cardiomyopathy Sci Rep 2016 6 28101 27307080 PMC4910108
  110. [116]Gurha P Chen X Lombardi R Willerson JT Marian AJ Knockdown of plakophilin-2 downregulates miR-184 through CpG hypermethylation and suppression of the E2F1 pathway and leads to enhanced adipogenesis in vitro Circ Res 2016 119 731 50 27470638 PMC5010490
  111. [117]Yang Z Bowles NE Scherer SE Taylor MD Kearney DL Ge S Nadvoretskiy VV DeFreitas G Carabello B Brandon LI Godsel LM Green KJ Saffitz JE Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy Circ Res 2006 99 646 55 16917092
  112. [118]den Haan AD Tan BY Zikusoka MN Lladó LI Jain R Daly A Tichnell C James C Amat-Alarcon N Abraham T Russell SD Bluemke DA Calkins H Comprehensive desmosome mutation analysis in north americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy Circ Cardiovasc Genet 2009 2 428 35 20031617 PMC2801867
  113. [119]Bhonsale A Groeneweg JA James CA Dooijes D Tichnell C Jongbloed JD Murray B te Riele AS van den Berg MP Bikker H Atsma DE de Groot NM Houweling AC Impact of genotype on clinical course in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated mutation carriers Eur Heart J 2015 36 847 55 25616645
  114. [120]Lahtinen AM Lehtonen A Kaartinen M Toivonen L Swan H Widén E Lehtonen E Lehto VP Kontula K Plakophilin-2 missense mutations in arrhythmogenic right ventricular cardiomyopathy Int J Cardiol 2008 126 92 100 17521752
  115. [121]Bauce B Nava A Beffagna G Basso C Lorenzon A Smaniotto G De Bortoli M Rigato I Mazzotti E Steriotis A Marra MP Towbin JA Thiene G Multiple mutations in desmosomal proteins encoding genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia Heart Rhythm 2010 7 22 29 20129281
  116. [122]Bhuiyan ZA Jongbloed JD van der Smagt J Lombardi PM Wiesfeld AC Nelen M Schouten M Jongbloed R Cox MG van Wolferen M Rodriguez LM van Gelder IC Bikker H Desmoglein-2 and desmocollin-2 mutations in dutch arrhythmogenic right ventricular dysplasia/cardiomypathy patients: results from a multicenter study Circ Cardiovasc Genet 2009 2 418 27 20031616
  117. [123]Heuser A Plovie ER Ellinor PT Grossmann KS Shin JT Wichter T Basson CT Lerman BB Sasse-Klaassen S Thierfelder L MacRae CA Gerull B Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy Am J Hum Genet 2006 79 1081 88 17186466 PMC1698714
  118. [124]Merner ND Hodgkinson KA Haywood AF Connors S French VM Drenckhahn JD Kupprion C Ramadanova K Thierfelder L McKenna W Gallagher B Morris-Larkin L Bassett AS Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene Am J Hum Genet 2008 82 809 21 18313022 PMC2427209
  119. [125]Klauke B Kossmann S Gaertner A Brand K Stork I Brodehl A Dieding M Walhorn V Anselmetti D Gerdes D Bohms B Schulz U Zu Knyphausen De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy Hum Mol Genet 2010 19 4595 607 20829228
  120. [126]Lorenzon A Beffagna G Bauce B De Bortoli M Li Mura IE Calore M Dazzo E Basso C Nava A Thiene G Rampazzo A Desmin mutations and arrhythmogenic right ventricular cardiomyopathy Am J Cardiol 2013 111 400 05 23168288 PMC3554957
  121. [127]Tiso N Stephan DA Nava A Bagattin A Devaney JM Stanchi F Larderet G Brahmbhatt B Brown K Bauce B Muriago M Basso C Thiene G Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2) Hum Mol Genet 2001 10 189 94 11159936
  122. [128]Beffagna G Occhi G Nava A Vitiello L Ditadi A Basso C Bauce B Carraro G Thiene G Towbin JA Danieli GA Rampazzo A Regulatory mutations in transforming growth factor-beta3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1 Cardiovasc Res 2005 65 366 73 15639475
  123. [129]Quarta G Syrris P Ashworth M Jenkins S Zuborne Alapi K Morgan J Muir A Pantazis A McKenna WJ Elliott PM Mutations in the Lamin A/C gene mimic arrhythmogenic right ventricular cardiomyopathy Eur Heart J 2012 33 1128 36 22199124
  124. [130]Taylor M Graw S Sinagra G Barnes C Slavov D Brun F Pinamonti B Salcedo EE Sauer W Pyxaras S Anderson B Simon B Bogomolovas J Genetic variation in titin in arrhythmogenic right ventricular cardiomyopathy-overlap syndromes Circulation 2011 124 876 85 21810661 PMC3167235
  125. [131]van der Zwaag PA van Rijsingen IA Asimaki A Jongbloed JD van Veldhuisen DJ Wiesfeld AC Cox MG van Lochem LT de Boer RA Hofstra RM Christiaans I van Spaendonck-Zwarts KY Lekanne dit Deprez RH Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy Eur J Heart Fail 2012 14 1199 207 22820313 PMC3475434

Cited by

Sorted by citations

Authors
Lorenzon, A., Calore, M., Poloni, G., De Windt, L. J., Braghetta, P., & Rampazzo, A.
Affiliations
  • University of Padua (IT)
  • Maastricht University (NL)
  • Maastricht University, Department of Cardiology, Maastricht, The Netherlands
Corresponding author
Rampazzo, Alessandra
ORCID
Venue
Oncotarget
Publisher
Impact Journals, LLC
Published
2017-04-27
Volume
8
Issue
36
Pages
60640-60655
ISSN
1949-2553 (ISSN-L)
DOI
10.18632/oncotarget.17457
PMC
PMC5601168
OpenAlex
W2607924217
Cited by
64
References
6
Citations by year
2026: 6 · 2025: 7 · 2024: 5 · 2023: 5 · 2022: 10 · 2021: 10 · 2020: 5 · 2019: 8 · 2018: 6 · 2017: 2
FWCI
0.81
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Oncotarget (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Publications (Maastricht University) (publishedVersion, cc-by)
  • Padua Research Archive (University of Padova) (submittedVersion)
  • Research Publications (Maastricht University) (submittedVersion, cc-by)
Funders
  • Università degli Studi di Padova (CPDA133979/13)
  • Regione del Veneto
  • Horizon 2020 Framework Programme (H2020‐MSCAIF‐2014, H2020-MSCA, MSCA-IF-2014)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Effects of Exercise
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
Keywords
Wnt/β-catenin signaling, arrhythmogenic cardiomyopathy, microRNA, epigenetic regulation, intercalated discs, ventricular arrhythmias, fibrofatty tissue, myocyte injury, therapeutic target, myocardial fibrosis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review