N-cadherin haploinsufficiency affects cardiac gap junctions and arrhythmic susceptibility

被引:65
|
作者
Li, Jifen [1 ]
Levin, Mark D. [3 ]
Xiong, Yanming [1 ]
Petrenko, Nataliya [2 ]
Patel, Vickas V. [2 ,3 ]
Radice, Glenn L. [1 ,3 ]
机构
[1] Univ Penn, Sch Med, Ctr Res Reprod & Womens Hlth, Philadelphia, PA 19104 USA
[2] Univ Penn, Sch Med, Div Cardiovasc Med, Philadelphia, PA 19104 USA
[3] Univ Penn, Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA
关键词
arrhythmia; cell communication; cadherin; connexin; gap junction;
D O I
10.1016/j.yjmcc.2007.11.013
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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. (C) 2007 Elsevier Inc. All rights reserved.
引用
收藏
页码:597 / 606
页数:10
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