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.

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Acknowledgments

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

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Correspondence to Zouhair Aherrahrou.

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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’.

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

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Aherrahrou, Z., Schlossarek, S., Stoelting, S. et al. Knock-out of nexilin in mice leads to dilated cardiomyopathy and endomyocardial fibroelastosis. Basic Res Cardiol 111, 6 (2016). https://doi.org/10.1007/s00395-015-0522-5

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Keywords

  • Dilated cardiomyopathy
  • Heart failure
  • Endocardial fibroelastosis
  • Nexilin
  • Knock-out mice