Cardiac arrhythmias associated with structural heart disease are a major cause of morbidity and mortality in the United States. The cadherin family of cell adhesion receptors, located in the adherens junction, interacts homophilically to mediate strong cell-cell adhesion and play a key role in the maintenance of tissue structure. The adhesive strength of cadherins is modulated by catenins, which mediate cadherin linkage to the actin cytoskeleton. We recently developed cardiac-restricted N-cadherin conditional knockout mice that exhibit severe conduction defects and sudden cardiac death. The long-term goal of this study is to determine the specific contribution of dysregulated cadherin/catenin intercellular coupling to the formation of the arrhythmogenic substrate and to understand the molecular mechanisms resulting in gap junctional remodeling. Toward this end, we will utilize conditional gene-targeted murine models to elucidate the role of the cadherin/catenin complex in stabilizing gap junctions in the working myocardium.
The specific aims are to: 1) Determine the importance of a-catenin in maintaining mechanical and electrical coupling between cardiomyocytes. 2) Determine the mechanism by which loss of N-cadherin leads to remodeling of gap junctions. 3) Determine if N-cadherin heterozygotes and N-cadherin/Cx43 compound heterozygotes are susceptible to stress-induced cardiac arrhythmias. 4) Determine the role of ?- catenin (plakoglobin) in maintaining gap junction stability. Patients suffering from Naxos disease have a mutant form of plakoglobin that causes arrhythmic right ventricular cardiomyopathy. A mouse model of Naxos disease will be generated to investigate the arrhythmogenic mechanism responsible for the sudden cardiac death in these patients. Knowledge gained from these experiments will provide a molecular framework for understanding the mechanism of arrhythmogenesis in heart disease. In turn our studies may lead to better screening methods to identify persons at risk of sudden death due to cardiac arrhythmia, and possibly to novel therapies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Przywara, Dennis
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Thomas Jefferson University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Swope, David; Li, Jifen; Radice, Glenn L (2013) Beyond cell adhesion: the role of armadillo proteins in the heart. Cell Signal 25:93-100
Swope, David; Cheng, Lan; Gao, Erhe et al. (2012) Loss of cadherin-binding proteins ?-catenin and plakoglobin in the heart leads to gap junction remodeling and arrhythmogenesis. Mol Cell Biol 32:1056-67
Li, Jifen; Goossens, Steven; van Hengel, Jolanda et al. (2012) Loss of ýýT-catenin alters the hybrid adhering junctions in the heart and leads to dilated cardiomyopathy and ventricular arrhythmia following acute ischemia. J Cell Sci 125:1058-67
Swope, David; Li, Jifen; Muller, Eliane J et al. (2012) Analysis of a Jup hypomorphic allele reveals a critical threshold for postnatal viability. Genesis 50:717-27
Cheng, Lan; Yung, Aaron; Covarrubias, Manuel et al. (2011) Cortactin is required for N-cadherin regulation of Kv1.5 channel function. J Biol Chem 286:20478-89
Li, Jifen; Swope, David; Raess, Natalia et al. (2011) Cardiac tissue-restricted deletion of plakoglobin results in progressive cardiomyopathy and activation of {beta}-catenin signaling. Mol Cell Biol 31:1134-44
Li, Jifen; Radice, Glenn L (2010) A new perspective on intercalated disc organization: implications for heart disease. Dermatol Res Pract 2010:207835
Hamad, Eman A; Li, Xue; Song, Jianliang et al. (2010) Effects of cardiac-restricted overexpression of the A(2A) adenosine receptor on adriamycin-induced cardiotoxicity. Am J Physiol Heart Circ Physiol 298:H1738-47
Stepniak, Ewa; Radice, Glenn L; Vasioukhin, Valeri (2009) Adhesive and signaling functions of cadherins and catenins in vertebrate development. Cold Spring Harb Perspect Biol 1:a002949
Li, Jifen; Levin, Mark D; Xiong, Yanming et al. (2008) N-cadherin haploinsufficiency affects cardiac gap junctions and arrhythmic susceptibility. J Mol Cell Cardiol 44:597-606