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.
BACKGROUND
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.


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.
Institut des Maladies Métaboliques et Cardiovasculaires, Institut National de la Santé et de la Recherche Médicale UMR 1048, Toulouse, France.
Gaël
G
Genet
Céline
C
Guilbeau-Frugier
Benjamin
B
Honton
Etienne
E
Dague
Michael D
MD
Schneider
Christelle
C
Coatrieux
Denis
D
Calise
Christelle
C
Cardin
Cécile
C
Nieto
Bruno
B
Payré
Caroline
C
Dubroca
Pauline
P
Marck
Christophe
C
Heymes
Alexandre
A
Dubrac
Dina
D
Arvanitis
Fabien
F
Despas
Marie-Françoise
MF
Altié
Marie-Hélène
MH
Seguelas
Marie-Bernadette
MB
Delisle
Alice
A
Davy
Jean-Michel
JM
Sénard
Atul
A
Pathak
Céline
C
Galés
D000818:Animals; D002450:Cell Communication / Q000502:physiology*; D002462:Cell Membrane / Q000502:physiology / Q000648:ultrastructure; D002478:Cells, Cultured; D003094:Collagen / Q000502:physiology / Q000648:ultrastructure; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology / Q000648:ultrastructure; D036387:Ephrin-B1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D012518:Sarcomeres / Q000000981:diagnostic imaging / Q000502:physiology; D014463:Ultrasonography
D036387:Ephrin-B1; D008565:Membrane Proteins; D003094:Collagen