Published online before print January 31, 2002, doi: 10.1161/01.RES.0000012223.86441.A1
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© 2002 American Heart Association, Inc.
Cellular Biology |
Reduction of Ito Causes Hypertrophy in Neonatal Rat Ventricular Myocytes
From the Departments of Physiology and Medicine (Z.K., C.Z., T.-T.T.N., P.H.B.), Heart and Stroke/Richard Lewar Center and Division of Cardiology, University Health Network, University of Toronto, Toronto, Canada; and the Division of Molecular Cardiovascular Biology (J.D.M.), Children’s Hospital Medical Center, Cincinnati, Ohio.
Correspondence to Peter H. Backx, DVM, PhD, or Carsten Zobel, MD, Heart and Stroke/Richard Lewar Center, Room 68, Fitzgerald Building, University of Toronto, 150 College St, Toronto, Ontario, Canada, M5S 3E2. E-mail p.backx{at}utoronto.ca or carsten.zobel@gmx.de
Prolonged action potential duration (APD) and decreased transient outward K+ current (Ito) as a result of decreased expression of Kv4.2 and Kv4.3 genes are commonly observed in heart disease. We found that treatment of cultured neonatal rat ventricular myocytes with Heteropoda Toxin3, a blocker of cardiac Ito, induced hypertrophy as measured using cell membrane capacitance and 3H-leucine uptake. To dissect the role of specific Ito-encoding genes in hypertrophy, Ito was selectively reduced by overexpressing mutant dominant-negative (DN) transgenes. Ito amplitude was reduced equally (by about 50%) by overexpression of DN Kv1.4 (Kv1.4N) or DN Kv4.2 (either Kv4.2N or Kv4.2W362F), but only DN Kv4.2 prolonged APD duration (at 1 Hz) and induced myocyte hypertrophy. This hypertrophy was prevented by coexpressing wild-type Kv4.2 channels (Kv4.2F) with the DN Kv4.2 genes, suggesting the hypertrophy is due to Ito reduction and not nonspecific effects of transgene overexpression. The hypertrophy caused by reductions of Kv4.x-based Ito was associated with increased activity of the calcium-dependent phosphatase, calcineurin, and could be prevented by coinfection with Ad-CAIN, a specific calcineurin inhibitor. The hypertrophy and calcineurin activation induced by Kv4.2N infection were prevented by blocking Ca2+ entry and excitability with verapamil or high [K+]o. Our studies suggest that reductions of Kv4.2/3-based Ito play a role in hypertrophy signaling by activation of calcineurin.
Key Words: cardiac myocyte • [Ca2+]i • transient outward K+ current • hypertrophy
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