Different roles of the cardiac Na+/Ca2+-exchanger in ouabain-induced inotropy, cell signaling, and hypertrophy
Different roles of the cardiac Na+/Ca2+-exchanger in ouabain-induced inotropy, cell signaling, and hypertrophy
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DOI：
10.1152/ajpheart.00462.2012
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发表时间：
2013-02-01
影响因子：
4.8
通讯作者：
Liu, Lijun
中科院分区：
文献类型：
--
作者：
Bai, Yan;Morgan, Eric E.;Liu, Lijun
杨文，杨文.心脏Na+/Ca 2+交换在哇巴因诱导的变力性、细胞信号传导和肥大中的不同作用。Am J Physiol Heart Circ Physiol 304：H427-H435，2013.首次发表于2012年11月30日; doi：10.1152/ajpheart.00462.2012.-以往的研究表明，洋地黄类药物作为心肌Na+/K+-ATP酶的特异性抑制剂，不仅具有正性肌力作用，而且可激活细胞信号通路，导致心肌细胞肥大。这项工作的一个主要目的是评估Na+/Ca 2 +-交换器，NCX 1，在上述两个看似相关的药物作用的作用。使用心室特异性敲除（KO）NCX 1的小鼠，哇巴因诱导的正性肌力在分离的野生型（Wt）心脏中明显降低。哇巴因还增加了Wt心肌细胞中的Ca 2+瞬时振幅，但在KO心肌细胞中不增加。哇巴因诱导的ERK 1/2的激活在Wt心肌细胞中被注意到，但在KO心肌细胞中未被注意到;然而，哇巴因激活了Wt和KO心肌细胞中的PI 3 K1 A和Akt。蛋白质合成率，作为衡量肥大，哇巴因增加在野生型和KO心肌细胞，这些药物的影响被阻止的PI 3 K抑制剂，但不是由MEK/ERK抑制剂。ET-1引起的肥大，而不是哇巴因诱导，伴随着BNP基因的上调在Wt和KO心肌细胞。这些结果表明：1）哇巴因的正性肌力作用需要NCX 1; 2）NCX 1和ERK 1/2激活与哇巴因诱导的肥大无关; 3）哇巴因通过激活PI 3 K1 A/Akt通路引起的肥大可能对心脏有益。
Bai Y, Morgan EE, Giovannucci DR, Pierre SV, Philipson KD, Askari A, Liu L. Different roles of the cardiac Na+/Ca2+-exchanger in ouabain-induced inotropy, cell signaling, and hypertrophy. Am J Physiol Heart Circ Physiol 304: H427-H435, 2013. First published November 30, 2012; doi: 10.1152/ajpheart.00462.2012.-Previous studies have shown that digitalis drugs, acting as specific inhibitors of cardiac Na+/K+-ATPase, not only cause positive inotropic effects, but also activate cell signaling pathways that lead to cardiac myocyte hypertrophy. A major aim of this work was to assess the role of Na+/Ca2+-exchanger, NCX1, in the above two seemingly related drug effects. Using a mouse with ventricular-specific knockout (KO) of NCX1, ouabain-induced positive inotropy that was evident in isolated wild-type (Wt) hearts was clearly reduced in KO hearts. Ouabain also increased Ca2+ transient amplitudes in Wt myocytes, but not in KO myocytes. Ouabain-induced activations of ERK 1/2 were noted in Wt myocytes, but not in KO myocytes; however, ouabain activated PI3K1A and Akt in both Wt and KO myocytes. Protein synthesis rate, as a measure of hypertrophy, was increased by ouabain in Wt and KO myocytes; these drug effects were prevented by a PI3K inhibitor but not by a MEK/ERK inhibitor. Hypertrophy caused by ET-1, but not that induced by ouabain, was accompanied by upregulation of BNP gene in Wt and KO myocytes. The findings indicate 1) the necessity of NCX1 for positive inotropic action of ouabain; 2) the irrelevance of NCX1 and ERK 1/2 activation to ouabain-induced hypertrophy; and 3) that hypertrophy caused by ouabain through the activation of PI3K1A/Akt pathway is likely to be beneficial to the heart.