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Basic Res Cardiol. 2016 Jan;111(1):6. doi: 10.1007/s00395-015-0522-5. Epub 2015 Dec 10.

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

Author information

1
Institute for Integrative and Experimental Genomics, University of Lübeck, 23562, Lübeck, Germany. zouhair.aherrahrou@iieg.uni-luebeck.de.
2
DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck/Hamburg, Germany. zouhair.aherrahrou@iieg.uni-luebeck.de.
3
University Heart Center Luebeck, 23562, Lübeck, Germany. zouhair.aherrahrou@iieg.uni-luebeck.de.
4
DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck/Hamburg, Germany.
5
Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
6
Institute for Integrative and Experimental Genomics, University of Lübeck, 23562, Lübeck, Germany.
7
Institute for Anatomy, University of Lübeck, Lübeck, Germany.
8
Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Technische Universität München, Munich, Germany.
9
German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany.
10
Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
11
Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Alte Akademie 8, 85354, Freising, Germany.
12
German Center for Diabetes Research (DZD), Ingostädter Landstr. 1, 85764, Neuherberg, Germany.
13
Department of Internal Medicine II, University Hospital Ulm, Ulm, Germany.
14
DZHK (German Research Centre for Cardiovascular Research), partner site Munich Heart Alliance (MHA), Munich, Germany.
15
University Heart Center Luebeck, 23562, Lübeck, Germany.

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; Endocardial fibroelastosis; Heart failure; Knock-out mice; Nexilin

PMID:
26659360
DOI:
10.1007/s00395-015-0522-5
[Indexed for MEDLINE]

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