Published online before print August 11, 2005, doi: 10.1161/01.RES.0000181132.11393.18
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© 2005 American Heart Association, Inc.
Integrative Physiology |
Cardiac-Specific Loss of N-Cadherin Leads to Alteration in Connexins With Conduction Slowing and Arrhythmogenesis
From the Center for Research on Reproduction and Women’s Health (J.L., I.K., Y.X., G.L.R.) and the Division of Cardiovascular Medicine (V.V.P., A.F.C., J.T.J.), University of Pennsylvania School of Medicine, Philadelphia, Penn; The Leon H. Charney Division of Cardiology (C.Y., G.E.M.), New York University School of Medicine, New York; and the Department of Pediatrics (J.D.M.), Children’s Hospital Medical Center, Cincinnati, Ohio.
Correspondence to Dr Glenn Radice, Center for Research on Reproduction and Women’s Health, University of Pennsylvania, 1355 Biomedical Research Building II/III, 421 Curie Blvd, Philadelphia, PA 19104. E-mail radice{at}mail.med.upenn.edu
The remodeling of ventricular gap junctions, as defined by changes in size, distribution, or function, is a prominent feature of diseased myocardium. However, the regulation of assembly and maintenance of gap junctions remains poorly understood. To investigate N-cadherin function in the adult myocardium, we used a floxed N-cadherin gene in conjunction with a cardiac-specific tamoxifen-inducible Cre transgene. The mutant animals appeared active and healthy until their sudden death 
2 months after deleting N-cadherin from the heart. Electrophysiologic analysis revealed abnormal conduction in the ventricles of mutant animals, including diminished QRS complex amplitude consistent with loss of electrical coupling in the myocardium. A significant decrease in the gap junction proteins, connexin-43 and connexin-40, was observed in N-cadherin–depleted myocytes. Perturbation of connexin function resulted in decreased ventricular conduction velocity, as determined by optical mapping. Our data suggest that perturbation of the N-cadherin/catenin complex in heart disease may be an underlying cause, leading to the establishment of the arrythmogenic substrate by destabilizing gap junctions at the cell surface.
Key Words: cell adhesion • arrhythmia • gap junctions • conditional knockout
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