Ngkelo et al. use a mast cell–deficient mouse model to reveal a protective role of mast cells in myocardial infarction, through regulation of the cardiac contractile machinery.

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...

C ardiac hypertrophy, the compensatory response of the heart to stress, is characterized by nonmitotic growth, the addition of new sarcomeres, and fetal gene expression. 1 However, prolonged hypertrophy of the myocardium can progress to heart failure (HF), a leading cause of morbidity and mortality, often associated with sudden cardiac death. 2-4Thus, understanding the signaling mechanisms that regulate pathological cardiac hypertrophy may lead to a better treatment for patients with HF.The hypertrophic growth of the myocardium is typically initiated by signal transduction pathways in response to Background-Cardiac hypertrophy is an early hallmark during the clinical course of heart failure and is regulated by various signaling pathways. However, the molecular mechanisms that negatively regulate these signal transduction pathways remain poorly understood. Methods and Results-Here, we characterized Carabin, a protein expressed in cardiomyocytes that was downregulated in cardiac hypertrophy and human heart failure. Four weeks after transverse aortic constriction, Carabin-deficient (Carabin −/− ) mice developed exaggerated cardiac hypertrophy and displayed a strong decrease in fractional shortening (14.6±1.6% versus 27.6±1.4% in wild type plus transverse aortic constriction mice; P<0.0001). Conversely, compensation of Carabin loss through a cardiotropic adeno-associated viral vector encoding Carabin prevented transverse aortic constrictioninduced cardiac hypertrophy with preserved fractional shortening (39.9±1.2% versus 25.9±2.6% in control plus transverse aortic constriction mice; P<0.0001). Carabin also conferred protection against adrenergic receptor-induced hypertrophy in isolated cardiomyocytes. Mechanistically, Carabin carries out a tripartite suppressive function. Indeed, Carabin, through its calcineurin-interacting site and Ras/Rab GTPase-activating protein domain, functions as an endogenous inhibitor of calcineurin and Ras/extracellular signal-regulated kinase prohypertrophic signaling. Moreover, Carabin reduced Ca 2+ / calmodulin-dependent protein kinase II activation and prevented nuclear export of histone deacetylase 4 after adrenergic stimulation or myocardial pressure overload. Finally, we showed that Carabin Ras-GTPase-activating protein domain and calcineurin-interacting domain were both involved in the antihypertrophic action of Carabin. Conclusions-Our study identifies Carabin as a negative regulator of key prohypertrophic signaling molecules, calcineurin, Ras, and Ca 2+/calmodulin-dependent protein kinase II and implicates Carabin in the development of cardiac hypertrophy and failure. (Circulation. 2015;131:390-400.