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Knock-out of nexilin in mice leads to dilated cardiomyopathy and endomyocardial fibroelastosis

  • Zouhair AherrahrouEmail author
  • Saskia Schlossarek
  • Stephanie Stoelting
  • Matthias Klinger
  • Birgit Geertz
  • Florian Weinberger
  • Thorsten Kessler
  • Redouane Aherrahrou
  • Kristin Moreth
  • Raffi Bekeredjian
  • Martin Hrabě de Angelis
  • Steffen Just
  • Wolfgang Rottbauer
  • Thomas Eschenhagen
  • Heribert Schunkert
  • Lucie Carrier
  • Jeanette Erdmann
Original Contribution

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.

Keywords

Dilated cardiomyopathy Heart failure Endocardial fibroelastosis Nexilin Knock-out mice 

Notes

Acknowledgments

We would like to thank Sandra Wrobel, Annett Liebers and Maren Behrensen for their technical support.

Compliance with ethical standards

Funding sources

The generation and characterization of the Nexn KO mice was supported by grants from the Bundesministerium für Bildung und Forschung, NGFN and NGFN-plus and Infrafrontier grant (01KX1012) as well as from the DZHK (German Centre for Cardiovascular Research) and the German Ministry of Research and Education (BMBF). Furthermore the project was also supported by the Leducq Foundation (Research grant Nr. 11, CVD 04) and the Association Institut de Myologie (Paris). Current funding is provided by the German Federal Ministry of Education and Research (BMBF) in the context of the e:Med program (e:AtheroSysMed and sysINFLAME), the FP7 European Union project CVgenes@target (261123) and a grant from the Fondation Leducq (CADgenomics: Understanding Coronary Artery Disease Genes, 12CVD02. Further grants were received by the local focus program “Medizinische Genetik” of the Universität zu Lübeck. This study was also supported through the Deutsche Forschungsgemeinschaft (DFG) cluster of excellence ‘Inflammation at Interfaces’.

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest

Supplementary material

395_2015_522_MOESM1_ESM.docx (112 kb)
Supplementary material 1 (DOCX 111 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Zouhair Aherrahrou
    • 1
    • 2
    • 3
    Email author
  • Saskia Schlossarek
    • 2
    • 4
  • Stephanie Stoelting
    • 1
    • 2
  • Matthias Klinger
    • 5
  • Birgit Geertz
    • 2
    • 4
  • Florian Weinberger
    • 2
    • 4
  • Thorsten Kessler
    • 6
  • Redouane Aherrahrou
    • 1
    • 2
  • Kristin Moreth
    • 7
  • Raffi Bekeredjian
    • 8
  • Martin Hrabě de Angelis
    • 7
    • 9
    • 10
  • Steffen Just
    • 11
  • Wolfgang Rottbauer
    • 11
  • Thomas Eschenhagen
    • 2
    • 4
  • Heribert Schunkert
    • 6
    • 12
  • Lucie Carrier
    • 2
    • 4
  • Jeanette Erdmann
    • 1
    • 2
    • 3
  1. 1.Institute for Integrative and Experimental GenomicsUniversity of LübeckLübeckGermany
  2. 2.DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/KielLübeck/HamburgGermany
  3. 3.University Heart Center LuebeckLübeckGermany
  4. 4.Department of Experimental Pharmacology and Toxicology, Cardiovascular Research CenterUniversity Medical Center Hamburg-EppendorfHamburgGermany
  5. 5.Institute for AnatomyUniversity of LübeckLübeckGermany
  6. 6.Deutsches Herzzentrum München, Klinik für Herz- und KreislauferkrankungenTechnische Universität MünchenMunichGermany
  7. 7.German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum MünchenGerman Research Center for Environmental HealthNeuherbergGermany
  8. 8.Department of CardiologyUniversity of HeidelbergHeidelbergGermany
  9. 9.Chair of Experimental Genetics, School of Life Science WeihenstephanTechnische Universität MünchenFreisingGermany
  10. 10.German Center for Diabetes Research (DZD)NeuherbergGermany
  11. 11.Department of Internal Medicine IIUniversity Hospital UlmUlmGermany
  12. 12.DZHK (German Research Centre for Cardiovascular Research), partner site Munich Heart Alliance (MHA)MunichGermany

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