title: Loss of Axin2 results in impaired heart valve maturation and subsequent myxomatous valve disease.
abstract: Myxomatous valve disease (MVD) is the most common aetiology of primary mitral regurgitation. Recent studies suggest that defects in heart valve development can lead to heart valve disease in adults. Wnt/β-catenin signalling is active during heart valve development and has been reported in human MVD. The consequences of increased Wnt/β-catenin signalling due to Axin2 deficiency in postnatal valve remodelling and pathogenesis of MVD were determined.
  
  
  
  To investigate the role of Wnt/β-catenin signalling, we analysed heart valves from mice deficient in Axin2 (KO), a negative regulator of Wnt/β-catenin signalling. Axin2 KO mice display enlarged mitral and aortic valves (AoV) after birth with increased Wnt/β-catenin signalling and cell proliferation, whereas Sox9 expression and collagen deposition are decreased. At 2 months in Axin2 KO mice, the valve extracellular matrix (ECM) is stratified but distal AoV leaflets remain thickened and develop aortic insufficiency. Progressive myxomatous degeneration is apparent at 4 months with extensive ECM remodelling and focal aggrecan-rich areas, along with increased BMP signalling. Infiltration of inflammatory cells is also observed in Axin2 KO AoV prior to ECM remodelling. Overall, these features are consistent with the progression of human MVD. Finally, Axin2 expression is decreased and Wnt/β-catenin signalling is increased in myxomatous mitral valves in a murine model of Marfan syndrome, supporting the importance of Wnt/β-catenin signalling in the development of MVD.
  
  
  
  Altogether, these data indicate that Axin2 limits Wnt/β-catenin signalling after birth and allows proper heart valve maturation. Moreover, dysregulation of Wnt/β-catenin signalling resulting from loss of Axin2 leads to progressive MVD.
authors.affiliation: Division of Molecular Cardiovascular Biology, The Heart Institute, Cincinnati Children's Hospital Medical Center, ML7020, 240 Albert Sabin Way, Cincinnati, OH 45229, USA.
authors.forename: Alexia
authors.initials: A
authors.lastname: Hulin
authors.affiliation: Division of Cardiology, The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Vicky
authors.initials: V
authors.lastname: Moore
authors.affiliation: Division of Cardiology, The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: James
authors.affiliation: Division of Molecular Cardiovascular Biology, The Heart Institute, Cincinnati Children's Hospital Medical Center, ML7020, 240 Albert Sabin Way, Cincinnati, OH 45229, USA; katherine.yutzey@cchmc.org.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Yutzey
mesh_terms: D053674:Aggrecans / Q000378:metabolism; D000818:Animals; D001021:Aortic Valve / Q000002:abnormalities / Q000378:metabolism* / Q000503:physiopathology; D001022:Aortic Valve Insufficiency / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D060466:Axin Protein / Q000172:deficiency* / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D000071838:Fibrillin-1 / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D020022:Genetic Predisposition to Disease; D006330:Heart Defects, Congenital / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008382:Marfan Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018345:Mice, Knockout; D008943:Mitral Valve / Q000002:abnormalities / Q000378:metabolism* / Q000503:physiopathology; D008944:Mitral Valve Insufficiency / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009024:Morphogenesis; D009154:Mutation; D010641:Phenotype; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway; D054392:Adipokines
chemical_list: D053674:Aggrecans; D060466:Axin Protein; D019485:Bone Morphogenetic Proteins; D003094:Collagen; D000071838:Fibrillin-1; D055758:SOX9 Transcription Factor; C111729:Axin2 protein, mouse; C000605724:Fbn1 protein, mouse; D054392:Adipokines; C527933:Sox9 protein, mouse
keywords: Axin2 • Heart valve development • Myxomatous valve disease • ECM remodelling • Wnt/β-catenin signalling