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Modulation of action potential duration on myocyte hypertrophic pathways

Djamel Lebeche1, Roger Kaprielian, Roger Hajjar

  • 1Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, 02129, USA. dlebeche@partners.org

Journal of Molecular and Cellular Cardiology
|April 8, 2006
PubMed

Insights

Enhancing the transient outward potassium current (I(to)) by overexpressing Kv4.3 in cardiomyocytes inhibits angiotensin II-induced hypertrophy. This suggests modulating action potential duration is key in cardiac hypertrophy development.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Electrophysiology

Background:

  • Cardiac hypertrophy and failure are linked to prolonged action potential duration (APD).
  • Reduced hyperpolarizing current from calcium-independent transient outward K+ channels (I(to)) contributes to APD prolongation.
  • Angiotensin II (AngII) is a key mediator of cardiac hypertrophy.

Purpose of the Study:

  • To investigate the impact of manipulating I(to) and sodium/calcium exchanger (NCX) currents on cardiomyocyte hypertrophy induced by AngII.
  • To determine if distinct intracellular calcium patterns influence MAPkinase activation and cellular hypertrophy.
  • To explore the role of action potential duration in AngII-mediated cardiac hypertrophy.

Main Methods:

  • Cultured neonatal rat ventricular myocytes (NRVMs) were infected with adenoviruses for Kv4.3, Kv4.3 antisense, or NCX.
  • Hypertrophy was induced by incubating NRVMs with AngII.
  • Measurements included I(to) density, APD, Ca(2+) influx, protein expression (ANF, beta-MHC), and MAPkinase/calcineurin activation.

Main Results:

  • Overexpression of Kv4.3 increased I(to), shortened APD, reduced Ca(2+) influx, and inhibited AngII-induced hypertrophy markers.
  • Kv4.3 overexpression blocked ERK MAP kinases and calcineurin expression.
  • These effects were reversed by Kv4.3 antisense and NCX gene transfer.

Conclusions:

  • Enhanced I(to) function via Kv4.3 overexpression abrogates AngII-mediated hypertrophy in NRVMs.
  • Modulating action potential duration is a significant factor in cardiac hypertrophy development.
  • Targeting I(to) channels offers a potential therapeutic strategy for cardiac hypertrophy.

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