Published Online
on October 7, 2002

A more recent version of this article appeared on October 29, 2002

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Submitted on March 28, 2002
Revised on July 31, 2002
Accepted on August 2, 2002

Prevention of Hypertrophy by Overexpression of Kv4.2 in Cultured Neonatal Cardiomyocytes

Carsten Zobel MD, Zameneh Kassiri PhD, The-Tin T. Nguyen MsC, Yang Meng PhD, and Peter H. Backx DVM, PhD^*

From the Departments of Physiology and Medicine, Division of Cardiology University Health Network and Heart & Stroke Richard Lewar Centre, University of Toronto, Ontario, Canada. Dr Zobel is now at the Laboratory of Muscle Research and Molecular Cardiology, Clinic III for Internal Medicine, University of Cologne, Joseph-Stelzmann-str. 9, 50924 Cologne, Germany.

^* To whom correspondence should be addressed. E-mail: p.backx{at}utoronto.ca.

Background—Prolonged action potentials (APs) and decreased transient outward K⁺ currents (I_to) are consistent findings in hypertrophic myocardium. However, the connection of these changes with cardiac hypertrophy is unknown. The present study investigated the effects of changes in I_to and the associated alterations in AP on myocyte hypertrophy induced by phenylephrine.

Methods and Results—Chronic incubation of cultured neonatal ventricular rat myocytes (NVRMs) with phenylephrine (PE) reduced I_to density and prolonged AP duration, leading to a 2-fold increase in the net Ca²⁺ influx per beat and a 1.4-fold increase in Ca²⁺-transient amplitude. PE treatment of chronically paced (2-Hz) NVRM also induced increases in cell size, protein/DNA ratio, atrial natriuretic factor mRNA expression, as well as ß/ myosin mRNA ratio. These hypertrophic changes were associated with a 2.4-fold increase in activation of nuclear factor of activated T-cells (NFAT), indicating increased activity of the Ca²⁺-dependent phosphatase calcineurin. Overexpression of Kv4.2 channels using adenovirus prevented the AP duration prolongation as well as the increases in Ca²⁺ influx and Ca²⁺-transient amplitude induced by PE. Kv4.2 overexpression also prohibited the PE-induced increases in cell size, protein/DNA ratio, atrial natriuretic factor expression, ß/ myosin mRNA ratio, and NFAT activation.

Conclusions—Our results demonstrate that PE-mediated hypertrophy in NRVMs seems to require I_to reductions and AP prolongation associated with increased Ca²⁺ influx and Ca²⁺ transients as well as calcineurin activation. The clinical implications of these studies and the possible involvement of other signaling pathways are discussed.

Key words: action potentials • myocytes • ion channels • hypertrophy • calcium

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