Molecular basis of transient outward potassium current downregulation in human heart failure: A decrease in Kv4.3 mRNA correlates with a reduction in current density

S. Kääb, J. Dixon, J. Duc, D. Ashen, M. Näbauer, D. J. Beuckelmann, G. Steinbeck, D. McKinnon, G. F. Tomaselli

Research output: Contribution to journalArticle

Abstract

Background - Despite advances in medical therapy, congestive heart failure remains a major cause of death in the developed world. A disproportionate number of the deaths of patients with heart failure are sudden and presumed to be arrhythmic. Heart failure in humans and in animal models is associated with prolongation of the action potential duration (APD), the result of downregulation of K+ currents - prominently, the Ca2+-independent transient outward current (I(to)). The mechanism for the reduction of I(to) in heart failure is unknown. The K+ channel α-subunit Kv4.3, a homolog of the Drosophila Shal family, is most likely to encode all or part of the native cardiac I(to) in humans. Methods and Results - We used ribonuclease protection assays and whole-cell electrophysiological recording to study changes in the level of Kv4.3 mRNA and I(to) in human tissues and isolated ventricular myocytes, respectively. We found that the level of Kv4.3 mRNA decreased by 30% in failing hearts compared with nonfailing controls. Furthermore, this reduction correlated with the reduction in peak I(to) density measured in ventricular myocytes isolated from adjacent regions of the heart. There was no significant change in the steady-state level of any other mRNA studied (HERG, Kvl.4, Kir2.1, Kvβl.3, and the αlC subunit of the Ca2+ channel). mRNAs encoding Kvl.2, Kvl.5, and Kv2.1 were found in low abundance in human ventricle. Conclusions - These data provide further support for the hypothesis that Kv4.3 encodes all or part of the native cardiac I(to) in humans and that part of the downregulation of this current in heart failure may be transcriptionally regulated.

Original languageEnglish (US)
Pages (from-to)1383-1393
Number of pages11
JournalCirculation
Volume98
Issue number14
StatePublished - Oct 6 1998

Keywords

  • Currents
  • Heart failure
  • Potassium
  • Repolarization
  • Sodium

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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