Cardiac-specific loss of N-cadherin leads to alteration in connexins with conduction slowing and arrhythmogenesis.
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.
Li
Jifen
J
Center for Research on Reproduction and Women's Health, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Patel
Vickas V
VV
Kostetskii
Igor
I
Xiong
Yanming
Y
Chu
Antony F
AF
Jacobson
Jason T
JT
Yu
Cindy
C
Morley
Gregory E
GE
Molkentin
Jeffery D
JD
Radice
Glenn L
GL
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
D015820:Cadherins; D018031:Connexin 43; D017630:Connexins; D000097003:Gap Junction alpha-5 Protein