NFATc3-induced reductions in voltage-gated K+ currents after myocardial infarction

Charles F. Rossow, Elina Minami, Eric G. Chase, Charles E. Murry, Luis Fernando Santana

Research output: Contribution to journalArticle

76 Scopus citations

Abstract

Reductions in voltage-activated K+ (Kv) currents may underlie arrhythmias after myocardial infarction (MI). We investigated the role of β-adrenergic signaling and the calcineurin/NFAT pathway in mediating the reductions in Kv currents observed after MI in mouse ventricular myocytes. Kv currents were produced by the summation of 3 distinct currents: Ito, IKslow1, and IKslow2. At 48 hours after MI, we found a 4-fold increase in NFAT activity, which coincided with a decrease in the amplitudes of Ito, IKslow1, and IKslow2. Consistent with this, mRNA and protein levels of Kv1.5, 2.1, 4.2, and 4.3, which underlie IKslow1, IKslow2, and Ito, were decreased after MI. Administration of the β-blocker metoprolol prevented the activation of NFAT and the reductions in Ito, I Kslow1, and IKslow2 after MI. Cyclosporine, an inhibitor of calcineurin, also prevented the reductions in these currents after MI. Importantly, Kv currents did not change after MI in ventricular myocytes from NFATc3 knockout mice. Conversely, chronic β-adrenergic stimulation or expression of an activated NFATc3 decreased Kv currents to a similar extent as MI. Taken together, these data indicate that NFATc3 plays an essential role in the signaling pathway leading to reduced Ito, IKslow1, and IKslow2 after MI. We propose that increased β-adrenergic signaling after MI activates calcineurin and NFATc3, which decreases I to, IKslow1, and IKslow2 via a reduction in Kv1.5, Kv2.1, Kv4.2, and Kv4.3 expression.

Original languageEnglish (US)
Pages (from-to)1340-1350
Number of pages11
JournalCirculation Research
Volume94
Issue number10
DOIs
StatePublished - May 28 2004
Externally publishedYes

Keywords

  • Arrhythmias
  • Calcineurin
  • Heart failure

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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