α-E-Catenin Inactivation Disrupts the Cardiomyocyte Adherens Junction, Resulting in Cardiomyopathy and Susceptibility to Wall Rupture

Abstract

Background-␣-E-catenin is a cell adhesion protein, located within the adherens junction, thought to be essential in directly linking the cadherin-based adhesion complex to the actin cytoskeleton. Although ␣-E-catenin is expressed in the adherens junction of the cardiomyocyte intercalated disc, and perturbations in its expression are observed in models of dilated cardiomyopathy, its role in the myocardium remains unknown. Methods and Results-To determine the effects of ␣-E-catenin on cardiomyocyte ultrastructure and disease, we generated cardiac-specific ␣-E-catenin conditional knockout mice (␣-E-cat cKO). ␣-E-cat cKO mice displayed progressive dilated cardiomyopathy and unique defects in the right ventricle. The effects on cardiac morphology/function in ␣-E-cat cKO mice were preceded by ultrastructural defects in the intercalated disc and complete loss of vinculin at the intercalated disc. ␣-E-cat cKO mice also revealed a striking susceptibility of the ventricular free wall to rupture after myocardial infarction. Conclusions-These results demonstrate a clear functional role for ␣-E-catenin in the cadherin/catenin/vinculin complex in the myocardium in vivo. Ablation of ␣-E-catenin within this complex leads to defects in cardiomyocyte structural integrity that result in unique forms of cardiomyopathy and predisposed susceptibility to death after myocardial stress. These studies further highlight the importance of studying the role of ␣-E-catenin in human cardiac injury and cardiomyopathy in the future.

A unique and specific interaction between αT-catenin and plakophilin-2 in the area composita, the mixed-type junctional structure of cardiac intercalated discs

“…In vitro, ␣N-and ␣T-catenin can substitute for the adhesive functions f ␣E-catenin, but their restricted expression patterns indicate additional isoform-specific or synergistic functions. This hypothesis was recently confirmed by the inability of endogenous ␣T-catenin expression to rescue heart-specific ␣E-catenin knockout in mice (Sheikh et al, 2006). Ablation of ␣E-catenin expression leads to defects in cardiomyocyte structural integrity; this results in unique forms of cardiomyopathy and susceptibility of the heart wall to rupture after cardiac stress.…”

“…To mediate the normal cell-cell interaction between cardiomyocytes, which is indispensable for cardiac functionality, these three different junctional complexes must be properly organized in the intercalated discs. Knockout experiments revealed that absence of adherens junctions (Linask et al, 1997;Olson et al, 2002;Kostetskii et al, 2005;Sheikh et al, 2006) or desmosomes (Bierkamp et al, 1996;Ruiz et al, 1996;Grossmann et al, 2004) has devastating consequences for heart development and viability. Moreover, mutations in structural proteins that are involved in the organization of the intercalated disc often lead to cardiomyopathy and heart failure (Maeda et al, 1997;McKoy et al, 2000;Norgett et al, 2000;Ferreira-Cornwell et al, 2002;Gerull et al, 2004;Prakasa and Calkins, 2005;Awad et al, 2006a;Awad et al, 2006b;Heuser et al, 2006;Pilichou et al, 2006;Uzumcu et al, 2006;Yang et al, 2006).…”

Actin filament association at adherens junctions

“…In endothelial cells, the actin-binding region of α-catenin is also required for VE-cadherin stabilization and accumulation to cortical actin bundles (55). PAs were disrupted in cardiac-specific α-catenin conditional knockout mice, resulting in cardiomyopathy and susceptibility to wall rupture (56).…”

Intercellular Connections in the Heart: The Intercalated Disc

“…Although many of their suggested signaling roles originate from studies in non-cardiac cells, it is presumed that catenins may have similar regulatory activities at the ID of cardiomyocytes. In support of this, transgenic mice lacking either -or -catenin result in detrimental effects on the longevity of the animals, with phenotypes ranging from embryonic lethality to the development of early onset DCM (Haegel et al, 1995;Piven et al, 2011;Sheikh et al, 2006). Future studies are necessary to continue addressing this question.…”