title: Cardiac-specific loss of N-cadherin leads to alteration in connexins with conduction slowing and arrhythmogenesis.
abstract: 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 approximately 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.
authors.affiliation: Center for Research on Reproduction and Women's Health, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: Jifen
authors.initials: J
authors.lastname: Li
authors.forename: Vickas V
authors.initials: VV
authors.lastname: Patel
authors.forename: Igor
authors.initials: I
authors.lastname: Kostetskii
authors.forename: Yanming
authors.initials: Y
authors.lastname: Xiong
authors.forename: Antony F
authors.initials: AF
authors.lastname: Chu
authors.forename: Jason T
authors.initials: JT
authors.lastname: Jacobson
authors.forename: Cindy
authors.initials: C
authors.lastname: Yu
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Morley
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Radice
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D015820:Cadherins / Q000502:physiology*; D018031:Connexin 43 / Q000032:analysis* / Q000502:physiology; D017630:Connexins / Q000032:analysis* / Q000502:physiology; D016757:Death, Sudden, Cardiac / Q000209:etiology; D004562:Electrocardiography; D017629:Gap Junctions / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000737:chemistry*; D000097003:Gap Junction alpha-5 Protein
chemical_list: D015820:Cadherins; D018031:Connexin 43; D017630:Connexins; D000097003:Gap Junction alpha-5 Protein