Targeted expression of a dominant-negative K(v)4.2 K+ channel subunit in the mouse heart

Alan D. Wickenden, Paul Lee, Rajan Sah, Qian Huang, Glenn I. Fishman, Peter H. Backx

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101 Scopus citations


Action potential duration is prolonged in many forms of heart disease, often as a result of reductions in Ca2+-independent transient outward K+ currents (ie, I(to)). To examine the effects of a primary reduction in I(to) current in the heart, transgenic mice were generated that express a dominant- negative N-terminal fragment of the K(v)4.2 pore-forming potassium channel subunit under the control of the mouse α-myosin heavy chain promoter. Two of 6 founders died suddenly, and only 1 mouse successfully transmitted the transgene in mendelian fashion. Electrophysiological analysis at 2 to 4 weeks of age demonstrated that I(to) density was specifically reduced and action potential durations were prolonged in a subset of transgenic myocytes. The heterogeneous reduction in I(to) was accompanied by significant prolongation of monophasic action potentials. In vivo hemodynamic studies at this age revealed significant elevations in the mean arterial pressure, peak systolic ventricular pressures, and ±dP/dt, indicative of enhanced contractility. Surprisingly, by 10 to 12 weeks of age, transgenic mice developed clinical and hemodynamic evidence of congestive heart failure. Failing transgenic hearts displayed molecular and cellular remodeling, with evidence of hypertrophy, chamber dilatation, and interstitial fibrosis, and individual myocytes showed sharp reductions in I(to) and I(Kl) densities, action potential duration prolongation, and increased cell capacitance. Our results confirm that K(v)4.2 subunits contribute to I(to) in the mouse and demonstrate that manipulation of cardiac excitability may secondarily influence contractile performance.

Original languageEnglish
Pages (from-to)1067-1076
Number of pages10
JournalCirculation research
Issue number11
StatePublished - Nov 26 1999


  • Cardiac electrophysiology
  • Heart failure
  • K channel
  • Mouse
  • Transgenic


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