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

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...

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Main Authors: Aherrahrou, Zouhair (Author) , Schlossarek, Saskia (Author) , Stoelting, Stephanie (Author) , Klinger, Matthias (Author) , Geertz, Birgit (Author) , Weinberger, Florian (Author) , Kessler, Thorsten (Author) , Aherrahrou, Redouane (Author) , Moreth, Kristin (Author) , Bekeredjian, Raffi (Author) , Hrabě de Angelis, Martin (Author) , Just, Steffen (Author) , Rottbauer, Wolfgang (Author) , Eschenhagen, Thomas (Author) , Schunkert, Heribert (Author) , Carrier, Lucie (Author) , Erdmann, Jeanette (Author)
Format: Article (Journal)
Language:English
Published: 2016
In: Basic research in cardiology
Year: 2015, Volume: 111
ISSN:1435-1803
DOI:10.1007/s00395-015-0522-5
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1007/s00395-015-0522-5
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Author Notes:Zouhair Aherrahrou, 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
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Summary: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.
Item Description:Published online: 10 December 2015
Gesehen am 12.08.2020
Physical Description:Online Resource
ISSN:1435-1803
DOI:10.1007/s00395-015-0522-5

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