Expression of human ERG K + channels in the mouse heart exerts anti-arrhythmic activity

Anne Royer, Sophie Demolombe, Aziza El Harchi, Khaï Le Quang, Julien Piron, Gilles Toumaniantz, David Mazurais, Chloé Bellocq, Gilles Lande, Cécile Terrenoire, Howard K. Motoike, Jean Christophe Chevallier, Gildas Loussouarn, Colleen E Clancy, Denis Escande, Flavien Charpentier

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

The K + channel encoded by the human ether-à-go-go-related gene (HERG) is crucial for repolarization in the human heart. In order to investigate the impact of HERG current (I Kr) on the incidence of cardiac arrhythmias, we generated a transgenic mouse expressing HERG specifically in the heart. ECG recordings at baseline showed no obvious difference between transgenic and wild-type (WT) mice with the exception of the T wave, which was more negative in transgenic mice than in WT mice. E4031 (20 mg/kg) prolonged the QTc interval and flattened the T wave in transgenic mice, but not in WT mice. Injection of BaCl 2 (25 mg/kg) induced short runs of ventricular tachycardia in 9/10 WT mice, but not in transgenic animals. Atrial pacing reproducibly induced atrial tachyarrhythmias in 11/15 WT mice. In contrast, atrial arrhythmia was inducible in only 2/11 transgenic mice. When pretreated with dofetilide (10 mg/kg), transgenic mice were as sensitive to experimental arrhythmias as WT mice. Microelectrode studies showed that atrial action potentials have a steeper slope of duration-rate adaptation in WT than in transgenic mice. Transgenic mice were also characterized by a post-repolarization refractoriness, which could result from the substantial amount of I Kr subsisting after repolarization as assessed with action potential-clamp experiments and simulations with a model of the transgenic mouse action potential. HERG expression in the mouse heart can protect against experimental induction of arrhythmias. This is the first report of such a protective effect of HERG in vivo.

Original languageEnglish (US)
Pages (from-to)128-137
Number of pages10
JournalCardiovascular Research
Volume65
Issue number1
DOIs
StatePublished - Jan 1 2005
Externally publishedYes

Keywords

  • Arrhythmia
  • K channel
  • Repolarization
  • Transgenic animal models

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Royer, A., Demolombe, S., El Harchi, A., Le Quang, K., Piron, J., Toumaniantz, G., Mazurais, D., Bellocq, C., Lande, G., Terrenoire, C., Motoike, H. K., Chevallier, J. C., Loussouarn, G., Clancy, C. E., Escande, D., & Charpentier, F. (2005). Expression of human ERG K + channels in the mouse heart exerts anti-arrhythmic activity. Cardiovascular Research, 65(1), 128-137. https://doi.org/10.1016/j.cardiores.2004.09.030