1. Ephrin-B1 Is a Novel Specific Component of the Lateral Membrane of the Cardiomyocyte and Is Essential for the Stability of Cardiac Tissue Architecture Cohesion
- Author
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Christophe Heymes, Michael D. Schneider, Céline Galés, Benjamin Honton, Denis Calise, Alexandre Dubrac, Christelle Coatrieux, Alice Davy, Etienne Dague, Christelle Cardin, Jean-Michel Senard, Marie-Hélène Seguelas, Fabien Despas, Bruno Payré, Marie-Bernadette Delisle, Céline Guilbeau-Frugier, Dina N. Arvanitis, Gael Genet, Caroline Dubroca, Pauline Marck, Marie-Françoise Altié, Atul Pathak, Cécile Nieto, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut des Technologies Avancées en sciences du Vivant (ITAV), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), National Heart and Lung Institute, Imperial College London-British Heart Foundation, Centre de Microscopie Électronique Appliquée à la Biologie (CMEAB), Toulouse Réseau Imagerie-Genotoul ( TRI-Genotoul), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de biologie du développement (CBD), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Service Pharmacologie Clinique [CHU Toulouse], Pôle Santé publique et médecine publique [CHU Toulouse], Simon, Marie Francoise, Service d'histopathologie, CHU Toulouse [Toulouse], Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Toulouse Réseau Imagerie-Genotoul ( TRI-Genotoul), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre de Biologie Intégrative (CBI), and Laboratoire de pharmacologie médicale et clinique
- Subjects
Male ,Physiology ,MESH: Myocytes, Cardiac ,Cell Communication ,Matrix (biology) ,MESH: Mice, Knockout ,Extracellular matrix ,Mice ,MESH: Collagen ,Myocyte ,Myocytes, Cardiac ,MESH: Animals ,Cells, Cultured ,Ultrasonography ,Mice, Knockout ,0303 health sciences ,MESH: Sarcomeres ,030302 biochemistry & molecular biology ,Anatomy ,Cell biology ,medicine.anatomical_structure ,MESH: Models, Animal ,Models, Animal ,Collagen ,MESH: Endothelium, Vascular ,MESH: Membrane Proteins ,Cardiology and Cardiovascular Medicine ,MESH: Cells, Cultured ,Sarcomeres ,animal structures ,Ephrin-B1 ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Biology ,03 medical and health sciences ,MESH: Mice, Inbred C57BL ,MESH: Cell Communication ,Dystroglycan ,medicine ,Animals ,Ephrin ,MESH: Mice ,[SDV.BC] Life Sciences [q-bio]/Cellular Biology ,030304 developmental biology ,Pressure overload ,Basement membrane ,MESH: Ephrin-B1 ,Cell Membrane ,Erythropoietin-producing hepatocellular (Eph) receptor ,Membrane Proteins ,MESH: Male ,Mice, Inbred C57BL ,biology.protein ,Endothelium, Vascular ,sense organs ,MESH: Cell Membrane - Abstract
Rationale: Cardiac tissue cohesion relying on highly ordered cardiomyocytes (CM) interactions is critical because most cardiomyopathies are associated with tissue remodeling and architecture alterations. Objective: Eph/ephrin system constitutes a ubiquitous system coordinating cellular communications which recently emerged as a major regulator in adult organs. We examined if eph/ephrin could participate in cardiac tissue cyto-organization. Methods and Results: We reported the expression of cardiac ephrin-B1 in both endothelial cells and for the first time in CMs where ephrin-B1 localized specifically at the lateral membrane. Ephrin-B1 knock-out (KO) mice progressively developed cardiac tissue disorganization with loss of adult CM rod-shape and sarcomeric and intercalated disk structural disorganization confirmed in CM-specific ephrin-B1 KO mice. CMs lateral membrane exhibited abnormal structure by electron microscopy and notably increased stiffness by atomic force microscopy. In wild-type CMs, ephrin-B1 interacted with claudin-5/ZO-1 complex at the lateral membrane, whereas the complex disappeared in KO/CM-specific ephrin-B1 KO mice. Ephrin-B1 deficiency resulted in decreased mRNA expression of CM basement membrane components and disorganized fibrillar collagen matrix, independently of classical integrin/dystroglycan system. KO/CM-specific ephrin-B1 KO mice exhibited increased left ventricle diameter and delayed atrioventricular conduction. Under pressure overload stress, KO mice were prone to death and exhibited striking tissue disorganization. Finally, failing CMs displayed downregulated ephrin-B1/claudin-5 gene expression linearly related to the ejection fraction. Conclusions: Ephrin-B1 is necessary for cardiac tissue architecture cohesion by stabilizing the adult CM morphology through regulation of its lateral membrane. Because decreased ephrin-B1 is associated with molecular/functional cardiac defects, it could represent a new actor in the transition toward heart failure.
- Published
- 2012