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. ? ? ?
