Modulation of action potential duration on myocyte hypertrophic pathways

Djamel Lebeche, Roger Kaprielian, Roger Hajjar

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Prolongation of the action potential duration (APD) has consistently been observed in experimental models of cardiac hypertrophy and failure as well as in humans and is partially attributed to a reduction of a hyperpolarizing current provided by the calcium-independent transient outward K+ channel (Ito). In the present study, we examined the effects of manipulating ion channel currents (Ito and sodium/calcium exchanger (NCX)) and the associated alterations in action potential duration on cardiomyocyte hypertrophy and signaling induced by angiotensin II (AngII). Our aim was to examined whether distinct patterns of intracellular calcium manipulation could generate distinct patterns of MAPkinase activation and cellular hypertrophy. Cultured neonatal rat ventricular myocytes (NRVMs) were infected with Ad. β-gal/GFP, Ad.Kv4.3, Ad.Kv4.3 antisense or Ad.NCX adenoviruses and hypertrophy induced by incubation with AngII. Overexpression of Kv4.3 increased Ito density, shortened APD, decreased Ca2+ influx and inhibited AngII-induced 3H-leucine incorporation and ANF and β-MHC expression. These hypertrophic changes were also paralleled by blockade of ERK MAP kinases activation as well as calcineurin expression. These electrical and hypertrophic changes produced by overexpression of Kv4.3 were completely and significantly reversed by Kv4.3 antisense and NCX gene transfer. Our findings indicate that AngII-mediated hypertrophy response in NRVMs can be abrogated by an enhancement of Ito function through overexpression of Kv4.3 and that modulation of action potential duration can be important in the development of cardiac hypertrophy.

Original languageEnglish
Pages (from-to)725-735
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume40
Issue number5
DOIs
StatePublished - May 2006
Externally publishedYes

Keywords

  • Action potential duration
  • Angiotensin II
  • Gene transfer
  • Hypertrophic response,
  • Hypertrophy
  • Ito
  • K+ Channel
  • MAPKs
  • Signaling

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