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1.
J Mol Cell Cardiol ; 44(3): 597-606, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18201716

ABSTRACT

Cardiac-specific deletion of the murine gene (Cdh2) encoding the cell adhesion molecule, N-cadherin, results in disassembly of the intercalated disc (ICD) structure and sudden arrhythmic death. Connexin 43 (Cx43)-containing gap junctions are significantly reduced in the heart after depleting N-cadherin, therefore we hypothesized that animals expressing half the normal levels of N-cadherin would exhibit an intermediate phenotype. We examined the effect of N-cadherin haploinsufficiency on Cx43 expression and susceptibility to induced arrhythmias in mice either wild-type or heterozygous for the Cx43 (Gja1)-null allele. An increase in hypophosphorylated Cx43 accompanied by a modest decrease in total Cx43 protein levels was observed in the N-cadherin heterozygous mice. Consistent with these findings N-cadherin heterozygotes exhibited increased susceptibility to ventricular arrhythmias compared to wild-type mice. Quantitative immunofluorescence microscopy revealed a reduction in size of large Cx43-containing plaques in the N-cadherin heterozygous animals compared to wild-type. Gap junctions were further decreased in number and size in the N-cad/Cx43 compound heterozygous mice with increased arrhythmic susceptibility compared to the single mutants. The scaffold protein, ZO-1, was reduced at the ICD in N-cadherin heterozygous cardiomyocytes providing a possible explanation for the reduction in Cx43 plaque size. These data provide further support for the intimate relationship between N-cadherin and Cx43 in the heart, and suggest that germline mutations in the human N-cadherin (Cdh2) gene may predispose patients to increased risk of cardiac arrhythmias.


Subject(s)
Arrhythmias, Cardiac/metabolism , Cadherins/metabolism , Connexin 43/metabolism , Gap Junctions/metabolism , Animals , Arrhythmias, Cardiac/genetics , Arrhythmias, Cardiac/physiopathology , Blotting, Western , Cadherins/genetics , Cell Communication/genetics , Cells, Cultured , Connexin 43/genetics , Electrophysiology , Fluorescent Antibody Technique , Heterozygote , Membrane Proteins/metabolism , Mice , Muscle Cells/metabolism , Mutation , Myocardium/metabolism , Myocardium/pathology , Phosphoproteins/metabolism , Zonula Occludens-1 Protein , beta Catenin/metabolism
2.
Circ Res ; 97(5): 474-81, 2005 Sep 02.
Article in English | MEDLINE | ID: mdl-16100040

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.


Subject(s)
Arrhythmias, Cardiac/etiology , Cadherins/physiology , Connexin 43/analysis , Connexins/analysis , Myocytes, Cardiac/chemistry , Animals , Connexin 43/physiology , Connexins/physiology , Death, Sudden, Cardiac/etiology , Electrocardiography , Gap Junctions/physiology , Mice , Mice, Knockout , Gap Junction alpha-5 Protein
3.
Circ Res ; 96(3): 346-54, 2005 Feb 18.
Article in English | MEDLINE | ID: mdl-15662031

ABSTRACT

The structural integrity of the heart is maintained by the end-to-end connection between the myocytes called the intercalated disc. The intercalated disc contains different junctional complexes that enable the myocardium to function as a syncytium. One of the junctional complexes, the zonula adherens or adherens junction, consists of the cell adhesion molecule, N-cadherin, which mediates strong homophilic cell-cell adhesion via linkage to the actin cytoskeleton. To determine the function of N-cadherin in the working myocardium, we generated a conditional knockout containing loxP sites flanking exon 1 of the N-cadherin (Cdh2) gene. Using a cardiac-specific tamoxifen-inducible Cre transgene, N-cadherin was deleted in the adult myocardium. Loss of N-cadherin resulted in disassembly of the intercalated disc structure, including adherens junctions and desmosomes. The mutant mice exhibited modest dilated cardiomyopathy and impaired cardiac function, with most animals dying within two months after tamoxifen administration. Decreased sarcomere length and increased Z-line thickness were observed in the mutant hearts consistent with loss of muscle tension because N-cadherin was no longer available to anchor myofibrils at the plasma membrane. Ambulatory electrocardiogram monitoring captured the abrupt onset of spontaneous ventricular tachycardia, confirming that the deaths were arrhythmic in nature. A significant decrease in the gap junction protein, connexin 43, was observed in the N-cadherin-depleted hearts. This animal model provides the first demonstration of the hierarchical relationship of the structural components of the intercalated disc in the working myocardium, thus establishing N-cadherin's paramount importance in maintaining the structural integrity of the heart.


Subject(s)
Cadherins/genetics , Myocardium/chemistry , Myocardium/metabolism , Myocytes, Cardiac/chemistry , Myocytes, Cardiac/metabolism , Adherens Junctions/genetics , Animals , Arrhythmias, Cardiac/etiology , Arrhythmias, Cardiac/mortality , Breeding/methods , Cause of Death , Cell Adhesion/genetics , Desmosomes/genetics , Gene Deletion , Heart/physiopathology , Integrin beta1/biosynthesis , Mice , Mice, Inbred C57BL , Mice, Inbred Strains , Mice, Knockout , Mutation/genetics , Myocardium/pathology , Myocytes, Cardiac/pathology
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