Mena/VASP and αII-Spectrin complexes regulate cytoplasmic actin networks in cardiomyocytes and protect from conduction abnormalities and dilated cardiomyopathy

BACKGROUND: In the heart, cytoplasmic actin networks are thought to have important roles in mechanical support, myofibrillogenesis, and ion channel function. However, subcellular localization of cytoplasmic actin isoform
BACKGROUND: In the heart, cytoplasmic actin networks are thought to have important roles in mechanical support, myofibrillogenesis, and ion channel function. However, subcellular localization of cytoplasmic actin isoforms and proteins involved in the modulation of the cytoplasmic actin networks are elusive. Mena and VASP are important regulators of actin dynamics. Due to the lethal phenotype of mice with combined deficiency in Mena and VASP, however, distinct cardiac roles of the proteins remain speculative. In the present study, we analyzed the physiological functions of Mena and VASP in the heart and also investigated the role of the proteins in the organization of cytoplasmic actin networks.
RESULTS: We generated a mouse model, which simultaneously lacks Mena and VASP in the heart. Mena/VASP double-deficiency induced dilated cardiomyopathy and conduction abnormalities. In wild-type mice, Mena and VASP specifically interacted with a distinct αII-Spectrin splice variant (SH3i), which is in cardiomyocytes exclusively localized at Z- and intercalated discs. At Z- and intercalated discs, Mena and β-actin localized to the edges of the sarcomeres, where the thin filaments are anchored. In Mena/VASP double-deficient mice, β-actin networks were disrupted and the integrity of Z- and intercalated discs was markedly impaired.
CONCLUSIONS: Together, our data suggest that Mena, VASP, and αII-Spectrin assemble cardiac multi-protein complexes, which regulate cytoplasmic actin networks. Conversely, Mena/VASP deficiency results in disrupted β-actin assembly, Z- and intercalated disc malformation, and induces dilated cardiomyopathy and conduction abnormalities.
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Author:Peter M. Benz, Carla J. Merkel, Kristin Offner, Marco Abeßer, Melanie Ullrich, Tobias Fischer, Barbara Bayer, Helga Wagner, Stepan Gambaryan, Jeanine A. Ursitti, Ibrahim M. Adham, Wolfgang A. Linke, Stephan M. Feller, Ingrid Fleming, Thomas Renné, Stefan Frantz, Andreas Unger, Kai Schuh
URN:urn:nbn:de:hebis:30:3-316559
DOI:http://dx.doi.org/10.1186/1478-811X-11-56
ISSN:1478-811X
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=23937664
Parent Title (English):Cell communication and signaling
Publisher:BioMed Central
Place of publication:London
Document Type:Article
Language:English
Date of Publication (online):2013/08/12
Date of first Publication:2013/08/12
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2013/10/02
Tag:Actin; Dilated cardiomyopathy; Heart; Mena/VASP; Spectrin
Volume:11
Issue:56
Pagenumber:22
Note:
© 2013 Benz et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
HeBIS PPN:35321390X
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 2.0

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