The Wnt signaling pathway regulates physiological processes such as cell proliferation and differentiation, cell fate decisions, and stem cell maintenance and, thus, plays essential roles in embryonic development, but also in adult tissue homeostasis and repair. The Wnt signaling pathway has been associated with heart development and repair and has been shown to be crucially involved in proliferation and differentiation of progenitor cells into cardiomyocytes. The investigation of the role of the Wnt signaling pathway and the regulation of its expression/activity in atrial fibrillation has only just begun. The present minireview (I) provides original data regarding the expression of Wnt signaling components in atrial tissue of patients with atrial fibrillation or sinus rhythm and (II) summarizes the current state of knowledge of the regulation of Wnt signaling components’ expression/activity and the contribution of the various levels of the Wnt signal transduction pathway to the processes of the development, maintenance, and progression of atrial fibrillation.
SchinnerS.Wnt-signalling and the metabolic syndrome. Horm Metab Res2009;
41:159–63
7.
KadariAMekalaSWagnerNMalanDKothJDollKStappertLEckertDPeitzMMatthesJSassePHerzigSBrustleOErgunSEdenhoferF.Robust generation of cardiomyocytes from human iPS cells requires precise modulation of BMP and WNT signaling. Stem Cell Rev Rep2015;
11:560–9
8.
FoulquierSDaskalopoulosEPLluriGHermansKCMDebABlankesteijnWM.WNT signaling in cardiac and vascular disease. Pharmacol Rev2018;
70:68–141
9.
KannelWBAbbottRDSavageDDMcNamaraPM.Epidemiologic features of chronic atrial fibrillation: the Framingham study. N Engl J Med1982;
306:1018–22
10.
NattelS.New ideas about atrial fibrillation 50 years on. Nature2002;
415:219–26
11.
ShapiroWKleinG.Alterations in cardiac function immediately following electrical conversion of atrial fibrillation to normal sinus rhythm. Circulation1968;
38:1074–84
12.
BrandFNAbbottRDKannelWBWolfPA.Characteristics and prognosis of lone atrial fibrillation. 30-year follow-up in the Framingham study. JAMA1985;
254:3449–53
13.
HartRGHalperinJL.Atrial fibrillation and stroke: concepts and controversies. Stroke2001;
32:803–8
14.
FurbergCDPsatyBMManolioTAGardinJMSmithVERautaharjuPM.Prevalence of atrial fibrillation in elderly subjects (the cardiovascular health study). Am J Cardiol1994;
74:236–41
15.
SchottenUVerheuleSKirchhofPGoetteA.Pathophysiological mechanisms of atrial fibrillation: a translational appraisal. Physiol Rev2011;
91:265–325
16.
WijffelsMCKirchhofCJDorlandRAllessieMA.Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation1995;
92:1954–68
17.
AllessieMA.Atrial electrophysiologic remodeling: another vicious circle?J Cardiovasc Electrophysiol1998;
9:1378–93
18.
LaiLPSuMJLinJLLinFYTsaiCHChenYSHuangSKTsengYZLienWP.Down-regulation of L-type calcium channel and sarcoplasmic reticular Ca(2+)-ATPase mRNA in human atrial fibrillation without significant change in the mRNA of ryanodine receptor, calsequestrin and phospholamban: an insight into the mechanism of atrial electrical remodeling. J Am Coll Cardiol1999;
33:1231–7
19.
YueLMelnykPGaspoRWangZNattelS.Molecular mechanisms underlying ionic remodeling in a dog model of atrial fibrillation. Circulation Res1999;
84:776–84
20.
van der VeldenHMvan KempenMJWijffelsMCvan ZijverdenMGroenewegenWAAllessieMAJongsmaHJ.Altered pattern of connexin40 distribution in persistent atrial fibrillation in the goat. J Cardiovasc Electrophysiol1998;
9:596–607
21.
BukowskaALendeckelUKrohnAKeilhoffGten HaveSNeumannKHGoetteA.Atrial fibrillation down-regulates renal neutral endopeptidase expression and induces profibrotic pathways in the kidney. Europace2008;
10:1212–7
22.
FrustaciAChimentiCBellocciFMorganteERussoMAMaseriA.Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation1997;
96:1180–4
23.
LendeckelUArndtMWrengerSNeppleKHuthCAnsorgeSKleinHUGoetteA.Expression and activity of ectopeptidases in fibrillating human atria. J Mol Cell Cardiol2001;
33:1273–81
24.
ShinagawaKShiYFTardifJCLeungTKNattelS.Dynamic nature of atrial fibrillation substrate during development and reversal of heart failure in dogs. Circulation2002;
105:2672–8
25.
ThijssenVLAusmaJLiuGSAllessieMAvan EysGJBorgersM.Structural changes of atrial myocardium during chronic atrial fibrillation. Cardiovasc Pathol2000;
9:17–28
26.
ChilukotiRKGieseAMalenkeWHomuthGBukowskaAGoetteAFelixSBKanaanJWollertHGEvertKVerheuleSJaisPHatemSNLendeckelUWolkeC.Atrial fibrillation and rapid acute pacing regulate adipocyte/adipositas-related gene expression in the atria. Int J Cardiol2015;
187:604–13
27.
HaemersPHamdiHGuedjKSuffeeNFarahmandPPopovicNClausPLePrincePNicolettiAJalifeJWolkeCLendeckelUJaisPWillemsRHatemSN.Atrial fibrillation is associated with the fibrotic remodelling of adipose tissue in the subepicardium of human and sheep atria. Eur Heart J2017;
38:53–61
28.
VenteclefNGuglielmiVBalseEGaboritBCotillardAAtassiFAmourJLeprincePDutourAClementKHatemSN.Human epicardial adipose tissue induces fibrosis of the atrial myocardium through the secretion of adipo-fibrokines. Eur Heart J2015;
36:795–805a
29.
HatemSNSandersP.Epicardial adipose tissue and atrial fibrillation. Cardiovasc Res2014;
102:205–13
30.
BukowskaASchildLKeilhoffGHirteDNeumannMGardemannANeumannKHRöhlF-WHuthCGoetteALendeckelU.Mitochondrial dysfunction and redox signaling in atrial tachyarrhythmia. Exp Biol Med2008;
233:558–74
31.
GirerdNScridonABessiereFChauveauSGeloenABousselLMorelEChevalierP.Periatrial epicardial fat is associated with markers of endothelial dysfunction in patients with atrial fibrillation. PLoS One2013;
8:e77167
32.
GoetteAHoneycuttCLangbergJJ.Electrical remodeling in atrial fibrillation. Time course and mechanisms. Circulation1996;
94:2968–74
33.
JeganathanJSarafRMahmoodFPalABhasinMKHuangTMittelAKnioZSimonsRKhabbazKSenthilnathanVLiuDSellkeFMatyalR.Mitochondrial dysfunction in atrial tissue of patients developing postoperative atrial fibrillation. Ann Thor Surg2017;
104:1547–55
34.
SchildLBukowskaAGardemannAPolczykPKeilhoffGTägerMDudleySCKleinHUGoetteALendeckelU.Rapid pacing of embryoid bodies impairs mitochondrial ATP synthesis by a calcium-dependent mechanism – a model of in vitro differentiated cardiomyocytes to study molecular effects of tachycardia. Biochim Biophys Acta2006;
1762:608–15
35.
GoetteAKalmanJMAguinagaLAkarJCabreraJAChenSAChughSSCorradiDD'AvilaADobrevDFenelonGGonzalezMHatemSNHelmRHindricksGHoSYHoitBJalifeJKimYHLipGYMaCSMarcusGMMurrayKNogamiASandersPUribeWVan WagonerDRNattelSDocumentR.EHRA/HRS/APHRS/SOLAECE expert consensus on atrial cardiomyopathies: definition, characterization, and clinical implication. Europace2016;
18:1455–90
36.
BukowskaAHammwöhnerMSixdorfASchildLWiswedelIRöhlFWWolkeCLendeckelUAderkastCBochmannSChilukotiRKMostertzJBramlagePGoetteA.Dronedarone prevents microcirculatory abnormalities in the left ventricle during atrial tachypacing in pigs. Br J Pharmacol2012;
166:964–80
37.
ChilukotiRKMostertzJBukowskaAAderkastCFelixSBBuschMVolkerUGoetteAWolkeCHomuthGLendeckelU.Effects of irbesartan on gene expression revealed by transcriptome analysis of left atrial tissue in a porcine model of acute rapid pacing in vivo. Int J Cardiol2013;
168:2100–8
38.
PhesseTFlanaganDVincanE.Frizzled7: a promising Achilles' heel for targeting the wnt receptor complex to treat cancer. Cancers2016;
8:50
39.
NiehrsC.The complex world of WNT receptor signalling. Nat Rev Mol Cell Biol2012;
13:767–79
40.
ThrasivoulouCMillarMAhmedA.Activation of intracellular calcium by multiple wnt ligands and translocation of beta-catenin into the nucleus: a convergent model of wnt/Ca2+ and wnt/beta-catenin pathways. J Biol Chem2013;
288:35651–9
41.
CruciatCMNiehrsC.Secreted and transmembrane wnt inhibitors and activators. Cold Spring Harb Perspect Biol2013;
5:a015081
42.
DzialoERudnikMKoningRICzepielMTkaczKBaj-KrzyworzekaMDistlerOSiedlarMKaniaGBlyszczukP.WNT3a and WNT5a transported by exosomes activate WNT signaling pathways in human cardiac fibroblasts. Int J Mol Sci2019;
20:1436
43.
GuoFYiXLiMFuJLiS.Snail1 is positively correlated with atrial fibrosis in patients with atrial fibrillation and rheumatic heart disease. Exp Therap Med2017;
14:4231–7
44.
LvXLiJHuYWangSYangCLiCZhongG.Overexpression of miR-27b-3p targeting Wnt3a regulates the signaling pathway of wnt/beta-catenin and attenuates atrial fibrosis in rats with atrial fibrillation. Oxid Med Cell Longev2019;
2019:5703764
45.
HouJHuangSLongYHuangJYangSYaoJChenGYueYLiangMMeiBLiJWuZ.DACT2 regulates structural and electrical atrial remodeling in atrial fibrillation. J Thorac Dis2020;
12:2039–48
46.
PolontchoukLHaefligerJAEbeltBSchaeferTStuhlmannDMehlhornUKuhn-RegnierFDe VivieERDheinS.Effects of chronic atrial fibrillation on gap junction distribution in human and rat atria. J Am Coll Cardiol2001;
38:883–91
47.
NakashimaTOhkusaTOkamotoYYoshidaMLeeJKMizukamiYYanoM.Rapid electrical stimulation causes alterations in cardiac intercellular junction proteins of cardiomyocytes. Am J Physiol Heart Circ Physiol2014;
306:H1324–33
48.
NielsenJBThorolfsdottirRBFritscheLGZhouWSkovMWGrahamSEHerronTJMcCarthySSchmidtEMSveinbjornssonGSurakkaIMathisMRYamazakiMCrawfordRDGabrielsenMESkogholtAHHolmenOLLinMWolfordBNDeyRDalenHSulemPChungJHBackmanJDArnarDOThorsteinsdottirUBarasAO'DushlaineCHolstAGWenXHornsbyWDeweyFEBoehnkeMKheterpalSMukherjeeBLeeSKangHMHolmHKitzmanJShavitJAJalifeJBrummettCMTeslovichTMCareyTJGudbjartssonDFStefanssonKAbecasisGRHveemKWillerCJ.Biobank-driven genomic discovery yields new insight into atrial fibrillation biology. Nat Genet2018;
50:1234–9
49.
ChenJXuSLiWWuLWangLLiYZhouW.Nkx2 5 Insufficiency leads to atrial electrical remodeling through wnt signaling in HL-1 cells. Exp Therap Med2019;
18:4631–6
ThomasAMCabreraCPFinlayMLallKNoblesMSchillingRJWoodKMeinCABarnesMRMunroePBTinkerA.Differentially expressed genes for atrial fibrillation identified by RNA sequencing from paired human left and right atrial appendages. Physiol Genomics2019;
51:323–32
52.
ShtutmanMZhurinskyJSimchaIAlbaneseCD'AmicoMPestellRBen-Ze'evA.The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci U S A1999;
96:5522–7
LinRWuSZhuDQinMLiuX.Osteopontin induces atrial fibrosis by activating akt/GSK-3beta/beta-catenin pathway and suppressing autophagy. Life Sci2020;
245:117328
55.
FromAMScottCGChenHH.Changes in diastolic dysfunction in diabetes mellitus over time. Am J Cardiol2009;
103:1463–6
56.
NabauerMGerthALimbourgTSchneiderSOeffMKirchhofPGoetteALewalterTRavensUMeinertzTBreithardtGSteinbeckG.The registry of the German competence NETwork on atrial fibrillation: patient characteristics and initial management. Europace2009;
11:423–34
57.
VerdecchiaPReboldiGGattobigioRBentivoglioMBorgioniCAngeliFCarluccioESardoneMGPorcellatiC.Atrial fibrillation in hypertension: predictors and outcome. Hypertension2003;
41:218–23
58.
CardinSLiDThorin-TrescasesNLeungTKThorinENattelS.Evolution of the atrial fibrillation substrate in experimental congestive heart failure: angiotensin-dependent and -independent pathways. Cardiovasc Res2003;
60:315–25
GoetteAStaackTRöckenCArndtMGellerJCHuthCAnsorgeSKleinHULendeckelU.Increased expression of extracellular signal-regulated kinase and angiotensin-converting enzyme in human atria during atrial fibrillation. J Am Coll Cardiol2000;
35:1669–77
61.
GoetteAIttensonAHoffmannsPReekSHartungWKleinHAnsorgeSGellerJC.Increased expression of P-selectin in patients with chronic atrial fibrillation. Pacing Clin Electrophysiol2000;
23:1872–5
62.
TsaiCTLaiLPHwangJJChenWPChiangFTHsuKLTsengCDTsengYZLinJL.Renin-angiotensin system component expression in the HL-1 atrial cell line and in a pig model of atrial fibrillation. J Hypertension2008;
26:570–82
63.
GitauSCLiXZhaoDGuoZLiangHQianMLvLLiTXuBWangZZhangYXuCLuYDuZShanHYangB.Acetyl salicylic acid attenuates cardiac hypertrophy through wnt signaling. Front Med2015;
9:444–56
64.
YuLMengWDingJChengM.Klotho inhibits angiotensin II-induced cardiomyocyte hypertrophy through suppression of the AT1R/beta catenin pathway. Biochem Biophys Res Commun2016;
473:455–61
65.
YinLYaoJDengGWangXCaiWShenJ.Identification of candidate lncRNAs and circRNAs regulating WNT3/beta-catenin signaling in essential hypertension. Aging2020;
12:8261–88
66.
XiaoLXuBZhouLTanRJZhouDFuHLiAHouFFLiuY.Wnt/beta-catenin regulates blood pressure and kidney injury in rats. Biochim Biophys Acta Mol Basis Dis2019;
1865:1313–22
67.
ZhouLLiYHaoSZhouDTanRJNieJHouFFKahnMLiuY.Multiple genes of the renin-angiotensin system are novel targets of wnt/beta-catenin signaling. J Am Soc Nephrol2015;
26:107–20
68.
JinXGuoBYanJYangRChangLWangYMiaoCLiuSZhangHLiY.Angiotensin II increases secreted frizzled-related protein 5 (sFRP5) expression through AT1 receptor/rho/ROCK1/JNK signaling in cardiomyocytes. Mol Cell Biochem2015;
408:215–22
69.
ItohMTakeishiYNakadaSMiyamotoTTsunodaYTakahashiHKubotaITomoikeH.Long-term treatment with angiotensin II type 1 receptor antagonist, CV-11974, restores beta-catenin mRNA expression in volume-overloaded rabbit hearts. Heart Vessels2002;
17:36–41
70.
KawarazakiWMizunoRNishimotoMAyuzawaNHirohamaDUedaKKawakami-MoriFObaSMarumoTFujitaT.Salt causes aging-associated hypertension via vascular Wnt5a under klotho deficiency. J Clin Invest2020;
130:4152–66
71.
BenjaminEJLevyDVaziriSMD'AgostinoRBBelangerAJWolfPA.Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham heart study. JAMA1994;
271:840–4
72.
DublinSGlazerNLSmithNLPsatyBMLumleyTWigginsKPageRLHeckbertSR.Diabetes mellitus, glycemic control, and risk of atrial fibrillation. J Gen Intern Med2010;
25:853–8
73.
LatiniRStaszewskyLSunJLBethelMADisertoriMHaffnerSMHolmanRRChangFFGilesTDMaggioniAPRuttenGEStandlEThomasLTognoniLCaliffRMMcMurrayJJ.Incidence of atrial fibrillation in a population with impaired glucose tolerance: the contribution of glucose metabolism and other risk factors. A post hoc analysis of the nateglinide and valsartan in impaired glucose tolerance outcomes research trial. Am Heart J2013;
166:935–40.e1.
74.
ManningerMZweikerDDobrovnikMvan HunnikARohrerUZirngastBHerbstVMaechlerHSchottenUZirlikAScherrD.Acute hyperglycaemia is not associated with the development of atrial fibrillation in healthy pigs. Sci Rep2020;
10:11881
75.
ChaoTFSuenariKChangSLLinYJLoLWHuYFTuanTCTaiCTTsaoHMLiCHUengKCWuTJChenSA.Atrial substrate properties and outcome of catheter ablation in patients with paroxysmal atrial fibrillation associated with diabetes mellitus or impaired fasting glucose. Am J Cardiol2010;
106:1615–20
76.
KatoTYamashitaTSekiguchiASagaraKTakamuraMTakataSKanekoSAizawaTFuLT.What are arrhythmogenic substrates in diabetic rat atria?J Cardiovasc Electrophysiol2006;
17:890–4
77.
HuJLuXZhangXShaoXWangYChenJZhaoBLiSXuWWieC.Exogenous spermine attenuates myocardial fibrosis in diabetic cardiomyopathy by inhibiting endoplasmic reticulum stress and the canonical wnt signaling pathway. Cell Biol Int2020;
44:1660–70
78.
ZhaoZ.TGFbeta and wnt in cardiac outflow tract defects in offspring of diabetic pregnancies. Birth Defects Res B Dev Reprod Toxicol2014;
101:364–70
79.
Garcia-JimenezCGarcia-MartinezJMChocarro-CalvoADe la ViejaA.A new link between diabetes and cancer: enhanced WNT/beta-catenin signaling by high glucose. J Mol Endocrinol2014;
52:R51–66
80.
Durak-KozicaMPaszekEStepienEL.Role of the wnt signalling pathway in the development of endothelial disorders in response to hyperglycaemia. Expert Rev Mol Med2019;
21:e7
81.
ZhangYDedkovEITeplitskyDWeltmanNYPolCJRajagopalanVLeeBGerdesAM.Both hypothyroidism and hyperthyroidism increase atrial fibrillation inducibility in rats. Circulation2013;
6:952–9
82.
ReddyVTahaWKundumadamSKhanM.Atrial fibrillation and hyperthyroidism: a literature review. Indian Heart J2017;
69:545–50
83.
Bielecka-DabrowaAMikhailidisDPRyszJBanachM.The mechanisms of atrial fibrillation in hyperthyroidism. Thyroid Res2009;
2:4
84.
NieuwlaatRCapucciACammAJOlssonSBAndresenDDaviesDWCobbeSBreithardtGLe HeuzeyJYPrinsMHLevySCrijnsHJGM.Atrial fibrillation management: a prospective survey in ESC member countries: the euro heart survey on atrial fibrillation. Eur Heart J2005;
26:2422–34
85.
GudbjartssonDFArnarDOHelgadottirAGretarsdottirSHolmHSigurdssonAJonasdottirABakerAThorleifssonGKristjanssonKPalssonABlondalTSulemPBackmanVMHardarsonGAPalsdottirEHelgasonASigurjonsdottirRSverrissonJTKostulasKNgMCBaumLSoWYWongKSChanJCFurieKLGreenbergSMSaleMKellyPMacRaeCASmithEERosandJHillertJMaRCEllinorPTThorgeirssonGGulcherJRKongAThorsteinsdottirUStefanssonK.Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature2007;
448:353–7
86.
KahrPCPicciniIFabritzLGreberBScholerHScheldHHHoffmeierABrownNAKirchhofP.Systematic analysis of gene expression differences between left and right atria in different mouse strains and in human atrial tissue. PLoS One2011;
6:e26389
87.
Lozano-VelascoEHernandez-TorresFDaimiHSerraSAHerraizAHove-MadsenLAranegaAFrancoD.Pitx2 impairs calcium handling in a dose-dependent manner by modulating wnt signalling. Cardiovasc Res2016;
109:55–66
88.
Lozano-VelascoEWangensteenRQuesadaAGarcia-PadillaCOsorioJARuiz-TorresMDAranegaAFrancoD.Hyperthyroidism, but not hypertension, impairs PITX2 expression leading to wnt-microRNA-ion channel remodeling. PLoS One2017;
12:e0188473
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