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

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. (Circ Res. 2012;110:688-700.) Key Words: cardiomyocyte Ⅲ extracellular matrix Ⅲ lateral membrane Ⅲ cardiac tissue Ⅲ architecture Ⅲ heart failure T he heart constitutes a particular compact organ relying on strong tissue architecture cohesion and tight cellular interactions that ensure both mechanical and electrochemical coupling. Thus, most cardiopathies are associated with cardiac tissue remodeling and with alterations in architecture involved in disease progression toward heart failure (HF).Despite considerable advances in the field and development of effective drugs, HF still remains a prevalent condition associated with high morbidity and mortality rates. This could be in part explained by still imperfect knowledge of molecular basis at the origin of HF. In fact, to date, most research has focused on cardiomyocyte (CM) contractile dysfunction Original received December 15, 2011; revision received January 16, 2012; accepted January 25, 2012. In December 2011, the average time from submission to first decision for all original research pape...

Eph Receptors and Ephrins: Therapeutic Opportunities

“…Analysis of ephrin-B1 knockout mice also highlighted the importance of ephrin-B1 in maintaining the structural integrity of adult heart tissue by regulating the attachment of the cardiomyocyte lateral membrane to the surrounding extracellular matrix (27). This is a distinctive role for an ephrin, which does not involve Eph receptor binding (Figure 1B).…”

“…This is a distinctive role for an ephrin, which does not involve Eph receptor binding (Figure 1B). Since ephrin-B1 knockout causes not only heart morphological defects but also impaired electrical conduction and hypersensitivity to pressure overload, it will be important to assess the role of ephrin-B1 downregulation and gene mutations in heart disease as well as the utility of treatments potentiating ephrin-B1 function in the failing heart (27). In addition, intraperitoneal administration of ephrin-B2 Fc was reported to increase capillary density in the infarcted mouse myocardium, although the effects on functional recovery were not assessed (78).…”

Claudin-5 levels are reduced from multiple cell types in human failing hearts and are associated with mislocalization of ephrin-B1

“…However, the function of claudin-5 in the heart is unknown. A recent study identified ephrin-B1, a member of the transmembrane ephrin family that act as ligands for Eph receptor protein tyrosine kinases, to be in a complex with claudin-5 [12]. In an ephrin-B1 knockdown mouse model, claudin-5 is concomitantly reduced and is no longer localized normally in heart [12].…”

Recent Advances in Cardiac Myocyte Biology and Function

“…35,40 In heart failure research, most work has focused on myocyte contractile dysfunction, and relatively little attention has been given to the changes in tissue architecture and structural integrity. In this regard, the work of Genet et al 41 offers new insights into the role of cardiac architecture in mediating contractile dysfunction. They reported that ephrin-B1 is a component of the lateral membrane of the cardiac myocyte and is essential for cardiac tissue architecture cohesion by stabilizing their rod-shape morphology.…”

“…22,24,26,[49][50][51][52][53][54][55][56] New and innovative models of myocyte pathophysiology have emerged. 9,[27][28][29]33,57,58 Recent findings also emphasize the importance of relatively unappreciated aspects of cardiac myocyte biology, such as maintenance of structural integrity of cardiac myocytes 41 and the flux of its molecular constituents, 45,[59][60][61][62] the deregulation of which leads to pathological changes. In addition, recent literature highlights stress-induced activation of autophagy as a physiologically important cytoprotective mechanism in cardiac myocytes.…”