Published online before print November 20, 2003, doi: 10.1161/01.RES.0000108261.67979.2A
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Submitted on May 12, 2003
Revised on November 6, 2003
Accepted on November 11, 2003
Replacement of Connexin40 by Connexin45 in the Mouse. Impact on Cardiac Electrical Conduction
Sébastien Alcoléa ;
From the Laboratoire de Génétique et Physiologie du Développement (UMR CNRS 6545) (S.A., T.J.-G., D.G.), Institut de Biologie du Développement de Marseille, Université de la Méditerranée, Marseille, France; Department of Medical Physiology (H.v.R., H.J.), University Medical Center, Utrecht, The Netherlands; Neurologia Experimental (D.G., L.B.), Hospital Ramón y Cajal, Madrid, Spain; Interuniversity Cardiology Institute (J.d.B.), Utrecht, The Netherlands; Department of Anatomy and Embryology (W.L.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, and National Heart and Lung Institute (S.C.), Imperial College London, UK.
* To whom correspondence should be addressed. E-mail: gros{at}ibdm.univ-mrs.fr.
Gap junction channels, required for the propagation of cardiac impulse, are intercellular structures composed of connexins (Cx). Cx43, Cx40, and Cx45 are synthesized in the cardiomyocytes, and each of them has a unique cardiac expression pattern. Cx40 knock-in Cx45 mice were generated to explore the ability of Cx45 to replace Cx40, and to assess the functional equivalence of these two Cxs that are both expressed in the conduction system. ECGs revealed that the consequences resulting from the biallelic replacement of Cx40 by Cx45 were an increased duration of the P wave, and a prolonged and fractionated QRS complex. Epicardial mapping indicated that the conduction velocities (CV) in the right atrium and the ventricular myocardium, as well as conduction through the AV node, were unaffected. The significant reduction of the CV in the left atrium would be the most likely cause of the P-wave lengthening. In the right ventricle, a changed and prolonged activation in sinus rhythm was found in homozygous mutant mice, which may explain the prolongation and splitting of the QRS complex. Electrical mapping of the His bundle branches revealed that this was due to slow conduction measured in the right branch. The CV in the left branch was unchanged. Therefore, in the absence of Cx40, the upregulation of Cx45 in the heart results in a normal impulse propagation in the right atrium, the AV node, and the left His bundle branch only.
Key words: gap junction channels • connexins • cardiac conduction
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