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(Circulation Research. 2004;94:1340.)
© 2004 American Heart Association, Inc.

Cellular Biology

NFATc3-Induced Reductions in Voltage-Gated K⁺ Currents After Myocardial Infarction

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

From the Departments of Physiology and Biophysics (C.F.R., E.G.C., L.F.S.), Pathology (E.M., C.E.M.), and Medicine (E.M.), University of Washington, Seattle.

Correspondence to L.F. Santana, Department of Physiology and Biophysics, University of Washington, Box 357290, Seattle, WA 98195. E-mail santana{at}u.washington.edu

Reductions in voltage-activated K⁺ (Kv) currents may underlie arrhythmias after myocardial infarction (MI). We investigated the role of ß-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: I_to, I_Kslow1, and I_Kslow2. At 48 hours after MI, we found a 4-fold increase in NFAT activity, which coincided with a decrease in the amplitudes of I_to, I_Kslow1, and I_Kslow2. Consistent with this, mRNA and protein levels of Kv1.5, 2.1, 4.2, and 4.3, which underlie I_Kslow1, I_Kslow2, and I_to, were decreased after MI. Administration of the ß-blocker metoprolol prevented the activation of NFAT and the reductions in I_to, I_Kslow1, and I_Kslow2 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 ß-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 I_to, I_Kslow1, and I_Kslow2 after MI. We propose that increased ß-adrenergic signaling after MI activates calcineurin and NFATc3, which decreases I_to, I_Kslow1, and I_Kslow2 via a reduction in Kv1.5, Kv2.1, Kv4.2, and Kv4.3 expression.

Key Words: calcineurin • arrhythmias • heart failure

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