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(Circulation. 2006;114:1046-1055.)
© 2006 American Heart Association, Inc.

Molecular Cardiology

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

Farah Sheikh, PhD; Yinhong Chen, MD, PhD; Xingqun Liang, MD, PhD; Alain Hirschy, PhD; Antine E. Stenbit, MD, PhD; Yusu Gu, MS; Nancy D. Dalton, RDCS; Toshitaka Yajima, MD, PhD; Yingchun Lu, PhD; Kirk U. Knowlton, MD; Kirk L. Peterson, MD; Jean-Claude Perriard, PhD; Ju Chen, PhD

From the Department of Medicine (F.S., Y.C., X.L., A.E.S., Y.G., N.D.D., T.Y., Y.L., K.U.K., K.L.P., J.C.), University of California-San Diego, La Jolla, Calif, and Institute of Cell Biology (A.H., J.-C.P.), ETH, Swiss Federal Institute of Technology, Zurich, Switzerland.

Correspondence to Ju Chen, University of California-San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0613. E-mail juchen{at}ucsd.edu

Received April 17, 2006; revision received June 13, 2006; accepted June 30, 2006.

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.

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