title: Decreased WNT/β-catenin signalling contributes to the pathogenesis of dilated cardiomyopathy caused by mutations in the lamin a/C gene.
abstract: Cardiomyopathy caused by lamin A/C gene (LMNA) mutations (hereafter referred as LMNA cardiomyopathy) is characterized by cardiac conduction abnormalities and left ventricular systolic dysfunction predisposing to heart failure. Previous cardiac transcriptional profiling of LmnaH222P/H222P mouse, a small animal model of LMNA cardiomyopathy, suggested decreased WNT/β-catenin signalling. We confirmed decreased WNT/β-catenin signalling in the hearts of these mice by demonstrating decreased β-catenin and WNT proteins. This was correlated with increased expression of soluble Frizzled-related proteins that modulate the WNT/β-catenin signalling pathway. Hearts of LmnaH222P/H222P mice also demonstrated lowered expression of the gap junction connexin 43. Activation of WNT/β-catenin activity with 6-bromoindirubin-3'-oxime improved cardiac contractility and ameliorated intraventricular conduction defects in LmnaH222P/H222P mice, which was associated with increased expression of myocardial connexin 43. These results indicate that decreased WNT/β-catenin contributes to the pathophysiology of LMNA cardiomyopathy and that drugs activating β-catenin may be beneficial in affected individuals.
authors.affiliation: Department of Medicine, College of Physicians and Surgeons.|Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Le Dour
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, G.H. Pitié Salpêtrière, F-75651 Paris Cedex 13, France.
authors.forename: Coline
authors.initials: C
authors.lastname: Macquart
authors.affiliation: Department of Medicine, College of Physicians and Surgeons.
authors.forename: Fusako
authors.initials: F
authors.lastname: Sera
authors.affiliation: Department of Medicine, College of Physicians and Surgeons.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Homma
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, G.H. Pitié Salpêtrière, F-75651 Paris Cedex 13, France.
authors.forename: Gisele
authors.initials: G
authors.lastname: Bonne
authors.affiliation: Department of Medicine, College of Physicians and Surgeons.
authors.forename: John P
authors.initials: JP
authors.lastname: Morrow
authors.affiliation: Department of Medicine, College of Physicians and Surgeons.|Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Worman
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, G.H. Pitié Salpêtrière, F-75651 Paris Cedex 13, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Muchir
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D018031:Connexin 43 / Q000096:biosynthesis / Q000235:genetics*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D006333:Heart Failure / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D047908:Intracellular Signaling Peptides and Proteins; D034904:Lamin Type A / Q000235:genetics*; D051379:Mice; D009154:Mutation; D010091:Oximes / Q000008:administration & dosage; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D051153:Wnt Proteins / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics*; D000099274:Frizzled-Related Proteins
chemical_list: D018031:Connexin 43; D006023:Glycoproteins; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D034904:Lamin Type A; D010091:Oximes; D051153:Wnt Proteins; D051176:beta Catenin; D000099274:Frizzled-Related Proteins; C483321:6-bromoindirubin-3'-oxime; C495267:CTNNB1 protein, mouse; C543076:GJA1 protein, mouse; C494847:LMNA protein, human