Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 40, Issue 5, Pages 725-735Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.yjmcc.2006.01.018
Keywords
K+ channel; lto; action potential duration; hypertrophy; hypertrophic response; MAPKs; gene transfer; angiotensin II; signaling
Categories
Funding
- NHLBI NIH HHS [HL 71763, HL 57623, HL 076659] Funding Source: Medline
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Prolongation of the action potential duration (APD) has consistently been observed in experimental models of cardiac hypertrophy and failure as well as in humans and is partially attributed to a reduction of a hyperpolarizing current provided by the calcium-independent transient outward K+ channel (I-to). In the present study, we examined the effects of manipulating ion channel currents (I-to and sodium/calcium exchanger (NCX)) and the associated alterations in action potential duration on cardiomyocyte hypertrophy and signaling induced by angiotensin 11 (Ang11). Our aim was to examined whether distinct patterns of intracellular calcium manipulation could generate distinct patterns of MAPkinase activation and cellular hypertrophy. Cultured neonatal rat ventricular myocytes (NRVMs) were infected with Ad. beta-gal/GFP, Ad.Kv4.3, Ad.Kv4.3 antisense or Ad.NCX adenoviruses and hypertrophy induced by incubation with AngII. Overexpression of Kv4.3 increased It, density, shortened APD, decreased Ca2+ influx and inhibited Ang11-induced H-3-leucine incorporation and ANF and beta-MHC expression. These hypertrophic changes were also paralleled by blockade of ERK MAP kinases activation as well as calcineurin expression. These electrical and hypertrophic changes produced by overexpression of Kv4.3 were completely and significantly reversed by Kv4.3 antisense and NCX gene transfer. Our findings indicate that AngII-mediated hypertrophy response in NRVMs can be abrogated by an enhancement of I-to function through overexpression of Kv4.3 and that modulation of action potential duration can be important in the development of cardiac hypertrophy. (c) 2006 Elsevier Ltd. All rights reserved.
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