Cardiovascular Research Advance Access [Accepted Manuscript] published online on December 4, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm083
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Gap junction remodeling in human heart failure is associated with increased interaction of connexin43 with ZO-1
National Heart and Lung Institute, Imperial College London
* Corresponding author: Nicholas J Severs, Cardiac Medicine, National Heart & Lung Institute, Imperial College London, Guy Scadding Building, Dovehouse Street, London SW3 6LY, UK. E-mail n.severs{at}imperial.ac.uk; Tel +44(0)2073518140; Fax +44(0)2073518476
Aims: Remodeling of gap junctions, involving reduction of total gap junction quantity and down-regulation of connexin43 (Cx43), contributes to the arrhythmic substrate in congestive heart failure. However, little is known of the underlying mechanisms. Recent studies from in vitro systems suggest that the connexin-interacting protein zonula occludens-1 (ZO-1) is a potential mediator of gap junction remodeling. We therefore examined the hypothesis that ZO-1 contributes to reduced expression of Cx43-gap junctions in congestive heart failure.
Methods and results: Left ventricular myocardium from healthy control human hearts (n=5) was compared with that of explanted hearts from transplant patients with end-stage congestive heart failure due to idiopathic dilated cardiomyopathy (DCM; n=5) or ischemic cardiomyopathy (ICM; n=5). Immunoconfocal and immuno-electron microscopy showed that ZO-1 is specifically localized to the intercalated disk of cardiomyocytes in control and failing ventricles. ZO-1 protein levels were significantly increased in both DCM and ICM (P=0.0025), showing a significant, negative correlation to Cx43 levels (P=0.0029). There was, however, no significant alteration of ZO-1 mRNA (P=0.537). Double immunolabeling demonstrated that a proportion of ZO-1 label is co-localized with Cx43, and that co-localization of Cx43 with ZO-1 is significantly increased in the failing ventricle (P=0.003). Interaction between the two proteins was confirmed by co-immunoprecipitation. The proportion of Cx43 that co?immunoprecipitates with ZO-1 was significantly increased in the failing heart.
Conclusion: Our findings suggest that ZO-1, by interacting with Cx43, plays a role in the down-regulation and decreased size of Cx43 gap junctions in congestive heart failure.
Time for primary review: 15
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  N. J. Severs, A. F. Bruce, E. Dupont, and S. Rothery Remodelling of gap junctions and connexin expression in diseased myocardium Cardiovasc Res, October 1, 2008; 80(1): 9 - 19. [Abstract] [Full Text] [PDF]
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