Lebeche Djamel, Kaprielian Roger, Hajjar Roger
Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, 02129, USA.
J Mol Cell Cardiol. 2006 May;40(5):725-35. doi: 10.1016/j.yjmcc.2006.01.018.
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.
在心脏肥大和衰竭的实验模型以及人类中，一直观察到动作电位时程（APD）延长，这部分归因于钙非依赖性瞬时外向钾通道（I(to)）提供的超极化电流减少。在本研究中，我们研究了操纵离子通道电流（I(to)和钠/钙交换体（NCX））以及动作电位时程的相关改变对血管紧张素II（AngII）诱导的心肌细胞肥大和信号传导的影响。我们的目的是研究细胞内钙操纵的不同模式是否能产生丝裂原活化蛋白激酶（MAP激酶）激活和细胞肥大的不同模式。培养的新生大鼠心室肌细胞（NRVMs）用Ad.β-半乳糖苷酶/绿色荧光蛋白（Ad.β-gal/GFP）、Ad.Kv4.3、Ad.Kv4.3反义或Ad.NCX腺病毒感染，并与AngII孵育诱导肥大。Kv4.3的过表达增加了I(to)密度，缩短了APD，减少了Ca(2+)内流，并抑制了AngII诱导的（3）H-亮氨酸掺入以及心房钠尿肽（ANF）和β-肌球蛋白重链（β-MHC）表达。ERK MAP激酶激活以及钙调神经磷酸酶表达的阻断也与这些肥大变化平行。Kv4.3反义及NCX基因转移完全且显著地逆转了Kv4.3过表达所产生的这些电和肥大变化。我们的研究结果表明，通过Kv4.3过表达增强I(to)功能可消除NRVMs中AngII介导的肥大反应，并且动作电位时程的调节在心脏肥大的发展中可能很重要。
