Published online before print August 11, 2005, doi: 10.1161/01.RES.0000181132.11393.18
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on February 24, 2005
Revised on July 27, 2005
Accepted on July 28, 2005
Cardiac-Specific Loss of N-Cadherin Leads to Alteration in Connexins With Conduction Slowing and Arrhythmogenesis
Jifen Li ;
From the Center for Research on Reproduction and Women’s Health (J.L., I.K., Y.X., G.L.R.) and the Division of Cardiovascular Medicine (V.V.P., A.F.C., J.T.J.), University of Pennsylvania School of Medicine, Philadelphia, Penn; The Leon H. Charney Division of Cardiology (C.Y., G.E.M.), New York University School of Medicine, New York; and the Department of Pediatrics (J.D.M.), Children’s Hospital Medical Center, Cincinnati, Ohio.
* To whom correspondence should be addressed. E-mail: radice{at}mail.med.upenn.edu.
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 
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.
Key words: cell adhesion • arrhythmia • gap junctions • conditional knockout
This article has been cited by other articles:
 |
|
 |
|
  A. N. Smith, L.-A. Miller, G. Radice, R. Ashery-Padan, and R. A. Lang Stage-dependent modes of Pax6-Sox2 epistasis regulate lens development and eye morphogenesis Development, September 1, 2009; 136(17): 2977 - 2985. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Derangeon, N. Bourmeyster, I. Plaisance, C. Pinet-Charvet, Q. Chen, F. Duthe, M. R. Popoff, D. Sarrouilhe, and J.-C. Herve RhoA GTPase and F-actin Dynamically Regulate the Permeability of Cx43-made Channels in Rat Cardiac Myocytes J. Biol. Chem., November 7, 2008; 283(45): 30754 - 30765. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 U. Lisewski, Y. Shi, U. Wrackmeyer, R. Fischer, C. Chen, A. Schirdewan, R. Juttner, F. Rathjen, W. Poller, M. H. Radke, et al. The tight junction protein CAR regulates cardiac conduction and cell-cell communication J. Exp. Med., September 29, 2008; 205(10): 2369 - 2379. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. F. Bruce, S. Rothery, E. Dupont, and N. J. Severs Gap junction remodelling in human heart failure is associated with increased interaction of connexin43 with ZO-1 Cardiovasc Res, March 1, 2008; 77(4): 757 - 765. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. J. Severs The Carboxy Terminal Domain of Connexin43: From Molecular Regulation of the Gap Junction Channel to Supramolecular Organization of the Intercalated Disk Circ. Res., December 7, 2007; 101(12): 1213 - 1215. [Full Text] [PDF]
|
|
|
|
 |
|
 A. E. Zemljic-Harpf, J. C. Miller, S. A. Henderson, A. T. Wright, A. M. Manso, L. Elsherif, N. D. Dalton, A. K. Thor, G. A. Perkins, A. D. McCulloch, et al. Cardiac-Myocyte-Specific Excision of the Vinculin Gene Disrupts Cellular Junctions, Causing Sudden Death or Dilated Cardiomyopathy Mol. Cell. Biol., November 1, 2007; 27(21): 7522 - 7537. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. A. Gustafson-Wagner, H. W. Sinn, Y.-L. Chen, D.-Z. Wang, R. S. Reiter, J. L.-C. Lin, B. Yang, R. A. Williamson, J. Chen, C.-I. Lin, et al. Loss of mXin{alpha}, an intercalated disk protein, results in cardiac hypertrophy and cardiomyopathy with conduction defects Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2680 - H2692. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Nygren, M. L. Olson, K. Y. Chen, T. Emmett, G. Kargacin, and Y. Shimoni Propagation of the cardiac impulse in the diabetic rat heart: reduced conduction reserve J. Physiol., April 15, 2007; 580(2): 543 - 560. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Zhou, J. Qu, X. P. Yi, K. Graber, L. Huber, X. Wang, A. M. Gerdes, and F. Li Upregulation of {gamma}-catenin compensates for the loss of beta-catenin in adult cardiomyocytes Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H270 - H276. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Kirchhof, L. Fabritz, M. Zwiener, H. Witt, M. Schafers, S. Zellerhoff, M. Paul, T. Athai, K.-H. Hiller, H. A. Baba, et al. Age- and Training-Dependent Development of Arrhythmogenic Right Ventricular Cardiomyopathy in Heterozygous Plakoglobin-Deficient Mice Circulation, October 24, 2006; 114(17): 1799 - 1806. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Sheikh, Y. Chen, X. Liang, A. Hirschy, A. E. Stenbit, Y. Gu, N. D. Dalton, T. Yajima, Y. Lu, K. U. Knowlton, et al. {alpha}-E-Catenin Inactivation Disrupts the Cardiomyocyte Adherens Junction, Resulting in Cardiomyopathy and Susceptibility to Wall Rupture Circulation, September 5, 2006; 114(10): 1046 - 1055. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Li, V. V. Patel, and G. L. Radice Dysregulation of cell adhesion proteins and cardiac arrhythmogenesis. Clin. Med. Res., March 1, 2006; 4(1): 42 - 52. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. E. Isakson, D. N. Damon, K. H. Day, Y. Liao, and B. R. Duling Connexin40 and connexin43 in mouse aortic endothelium: evidence for coordinated regulation Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H1199 - H1205. [Abstract] [Full Text] [PDF]
|
|