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

Cell Communication and Signaling

Research

Stephan M Feller¹  Helga Wagner²  Stefan Frantz²  Barbara Bayer²  Wolfgang A Linke³  Andreas Unger³  Thomas Renné⁴  Jeanine A Ursitti⁵  Ingrid Fleming⁶  Stepan Gambaryan⁷  Ibrahim M Adham⁸  Melanie Ullrich⁹  Kai Schuh⁹  Marco Abeßer⁹  Tobias Fischer⁹  Kristin Offner⁹  Carla J Merkel^1,10  Peter M Benz^1,11 

[1] Biological Systems Architecture Group, University of Oxford, OX3 9DS, Oxford, UK;Section Tumor Biology, Institute of Molecular Medicine, ZAMED, Martin-Luther-University Halle-Wittenberg, D-06120, Halle (Saale), Germany;Comprehensive Heart Failure Center, University of Würzburg, D-97070, Würzburg, Germany;Department of Cardiovascular Physiology, Ruhr University Bochum, D-44780, Bochum, Germany;Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, 17176, Stockholm, Sweden;Institute for Clinical Chemistry, University Hospital Eppendorf, D-20246, Hamburg, Germany;Department of Physiology, University of Maryland School of Medicine, 21201, Baltimore, MD, USA;Institute for Vascular Signalling, Goethe-University Frankfurt, D-60590, Frankfurt, Germany;Institute of Clinical Biochemistry and Pathobiochemistry, University of Würzburg, D-97070, Würzburg, Germany;Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia;Institute of Human Genetics, University of Göttingen, D-37073, Göttingen, Germany;Institute of Physiology I, University of Würzburg, D-97070, Würzburg, Germany;Institute of Physiology I, University of Würzburg, D-97070, Würzburg, Germany;Department of Neurology, University of Bonn, D-53105, Bonn, Germany;Institute of Physiology I, University of Würzburg, D-97070, Würzburg, Germany;Institute for Vascular Signalling, Goethe-University Frankfurt, D-60590, Frankfurt, Germany;

关键词: Actin;    Heart;    Mena/VASP;    Spectrin;    Dilated cardiomyopathy;   

DOI  :  10.1186/1478-811X-11-56

 received in 2013-01-16, accepted in 2013-08-06,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundIn 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.ResultsWe 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.ConclusionsTogether, 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.

【 授权许可】

CC BY   
© Benz et al.; licensee BioMed Central Ltd. 2013