Modulation of action potential duration on myocyte hypertrophic pathways.
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 II (AngII). 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 I(to) density, shortened APD, decreased Ca(2+) influx and inhibited AngII-induced (3)H-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.
Lebeche
Djamel
D
Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, 02129, USA. dlebeche@partners.org
Kaprielian
Roger
R
Hajjar
Roger
R
D000200:Action Potentials / Q000502:physiology*; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006984:Hypertrophy / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051672:Shal Potassium Channels / Q000096:biosynthesis; D015398:Signal Transduction; D019831:Sodium-Calcium Exchanger
D051672:Shal Potassium Channels; D019831:Sodium-Calcium Exchanger; D000804:Angiotensin II; D049452:Green Fluorescent Proteins; D019703:Calcineurin