title: Knock-out of nexilin in mice leads to dilated cardiomyopathy and endomyocardial fibroelastosis.
abstract: Cardiomyopathy is one of the most common causes of chronic heart failure worldwide. Mutations in the gene encoding nexilin (NEXN) occur in patients with both hypertrophic and dilated cardiomyopathy (DCM); however, little is known about the pathophysiological mechanisms and relevance of NEXN to these disorders. Here, we evaluated the functional role of NEXN using a constitutive Nexn knock-out (KO) mouse model. Heterozygous (Het) mice were inter-crossed to produce wild-type (WT), Het, and homozygous KO mice. At birth, 32, 46, and 22 % of the mice were WT, Het, and KO, respectively, which is close to the expected Mendelian ratio. After postnatal day 6, the survival of the Nexn KO mice decreased dramatically and all of the animals died by day 8. Phenotypic characterizations of the WT and KO mice were performed at postnatal days 1, 2, 4, and 6. At birth, the relative heart weights of the WT and KO mice were similar; however, at day 4, the relative heart weight of the KO group was 2.3-fold higher than of the WT group. In addition, the KO mice developed rapidly progressive cardiomyopathy with left ventricular dilation and wall thinning and decreased cardiac function. At day 6, the KO mice developed a fulminant DCM phenotype characterized by dilated ventricular chambers and systolic dysfunction. At this stage, collagen deposits and some elastin deposits were observed within the left ventricle cavity, which resembles the features of endomyocardial fibroelastosis (EFE). Overall, these results further emphasize the role of NEXN in DCM and suggest a novel role in EFE.
authors.affiliation: Institute for Integrative and Experimental Genomics, University of Lübeck, 23562, Lübeck, Germany. zouhair.aherrahrou@iieg.uni-luebeck.de.|DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck/Hamburg, Germany. zouhair.aherrahrou@iieg.uni-luebeck.de.|University Heart Center Luebeck, 23562, Lübeck, Germany. zouhair.aherrahrou@iieg.uni-luebeck.de.
authors.forename: Zouhair
authors.initials: Z
authors.lastname: Aherrahrou
authors.affiliation: DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck/Hamburg, Germany.|Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Schlossarek
authors.affiliation: Institute for Integrative and Experimental Genomics, University of Lübeck, 23562, Lübeck, Germany.|DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck/Hamburg, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Stoelting
authors.affiliation: Institute for Anatomy, University of Lübeck, Lübeck, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Klinger
authors.affiliation: DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck/Hamburg, Germany.|Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Geertz
authors.affiliation: DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck/Hamburg, Germany.|Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Weinberger
authors.affiliation: Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Technische Universität München, Munich, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Kessler
authors.affiliation: Institute for Integrative and Experimental Genomics, University of Lübeck, 23562, Lübeck, Germany.|DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck/Hamburg, Germany.
authors.forename: Redouane
authors.initials: R
authors.lastname: Aherrahrou
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Moreth
authors.affiliation: Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
authors.forename: Raffi
authors.initials: R
authors.lastname: Bekeredjian
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany.|Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Alte Akademie 8, 85354, Freising, Germany.|German Center for Diabetes Research (DZD), Ingostädter Landstr. 1, 85764, Neuherberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hrabě de Angelis
authors.affiliation: Department of Internal Medicine II, University Hospital Ulm, Ulm, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Just
authors.affiliation: Department of Internal Medicine II, University Hospital Ulm, Ulm, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Rottbauer
authors.affiliation: DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck/Hamburg, Germany.|Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
authors.affiliation: Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Technische Universität München, Munich, Germany.|DZHK (German Research Centre for Cardiovascular Research), partner site Munich Heart Alliance (MHA), Munich, Germany.
authors.forename: Heribert
authors.initials: H
authors.lastname: Schunkert
authors.affiliation: DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck/Hamburg, Germany.|Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Lucie
authors.initials: L
authors.lastname: Carrier
authors.affiliation: Institute for Integrative and Experimental Genomics, University of Lübeck, 23562, Lübeck, Germany.|DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck/Hamburg, Germany.|University Heart Center Luebeck, 23562, Lübeck, Germany.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Erdmann
mesh_terms: D000818:Animals; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004452:Echocardiography; D004695:Endocardial Fibroelastosis / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000172:deficiency*; D046529:Microscopy, Electron, Transmission; D016133:Polymerase Chain Reaction
chemical_list: D008840:Microfilament Proteins
keywords: Dilated cardiomyopathy; Endocardial fibroelastosis; Heart failure; Knock-out mice; Nexilin