p21-Activated kinase1 (Pak1) is a negative regulator of NADPH-oxidase 2 in ventricular myocytes.
p21-Activated kinase1 (Pak1) is a negative regulator of NADPH-oxidase 2 in ventricular myocytes.
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DOI：
10.1016/j.yjmcc.2013.12.017
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发表时间：
2014-02
影响因子：
5
通讯作者：
Banach, Kathrin
中科院分区：
文献类型：
--
作者：
DeSantiago, Jaime;Bare, Dan J.;Xiao, Lei;Ke, Yunbo;Solaro, R. John;Banach, Kathrin
关键词：
缺血条件降低p21激活的激酶（Pak 1）的活性，从而导致缺血活性增加。缺血期间触发的脑电活动是基于细胞离子平衡和细胞Ca 2+处理特性的变化。在本研究中，我们使用了分离的小鼠心室肌细胞（VM）缺乏的Pak 1（Pak 1-/-）的表达，以确定Pak 1影响的机制，在模拟缺血过程中的心肌活动的产生。在15分钟的模拟缺血过程中，野生型（WT）和Pak 1-/-VM的Ca 2+瞬时振幅和动力学没有显着变化。然而，Pak 1-/-VM表现出夸张的[Ca 2 +]i增加，这导致自发的Ca 2+释放事件和波。Pak 1-/-VM中的Ca 2+过载可以用钠钙交换器（NCX）的反向模式阻断剂（KB-R7943）、活性氧物质的细胞质清除剂（ROS; TEMPOL）或RAC 1抑制剂（NSC 23766）来抑制。细胞质ROS水平的测量显示，Pak 1-/-VM或用Pak 1抑制剂（IPA 3）处理的VM中Pak 1活性降低增强细胞ROS产生。在NADPH氧化酶2（NOX 2; p47 phox-/-）缺陷的VM或NOX 2被抑制的VM（gp 91 ds-tat）中，ROS的Pak 1依赖性增加减弱。电压钳记录显示Pak 1-/-VM中NCX活性增加，这依赖于增强的NOX 2诱导的ROS产生。Pak 1-/-VM中夸张的Ca 2+过载可以通过低浓度的哇巴因来模仿。总的来说，我们的数据表明，Pak 1是一个关键的负调节NOX 2依赖的ROS的生产和NCX活性的潜在ROS依赖性刺激可以使VM的Ca 2+超载的条件下，没有显着的变化兴奋收缩耦合是显而易见的。
Ischemic conditions reduce the activity of the p21-activated kinase (Pak1) resulting in increased arrhythmic activity. Triggered arrhythmic activity during ischemia is based on changes in cellular ionic balance and the cells Ca2+ handling properties. In the current study we used isolated mouse ventricular myocytes (VMs) deficient for the expression of Pak1 (Pak1-/-) to determine the mechanism by which Pak1 influences the generation of arrhythmic activity during simulated ischemia. The Ca2+ transient amplitude and kinetics did not significantly change in wild type (WT) and Pak1-/- VMs during 15 min of simulated ischemia. However, Pak1-/- VMs exhibited an exaggerated increase in [Ca2+]i, which resulted in spontaneous Ca2+ release events and waves. The Ca2+ overload in Pak1-/- VMs could be suppressed with a reverse mode blocker (KB-R7943) of the sodium calcium exchanger (NCX), a cytoplasmic scavenger of reactive oxygen species (ROS; TEMPOL) or a RAC1 inhibitor (NSC23766). Measurements of the cytoplasmic ROS levels revealed that decreased Pak1 activity in Pak1-/- VMs or VMs treated with the Pak1 inhibitor (IPA3) enhanced cellular ROS production. The Pak1 dependent increase in ROS was attenuated in VMs deficient for NADPH oxidase 2 (NOX2; p47phox-/-) or in VMs where NOX2 was inhibited (gp91ds-tat). Voltage clamp recordings showed increased NCX activity in Pak1-/- VMs that depended on enhanced NOX2 induced ROS production. The exaggerated Ca2+ overload in Pak1-/- VMs could be mimicked by low concentrations of ouabain. Overall our data show that Pak1 is a critical negative regulator of NOX2 dependent ROS production and that a latent ROS dependent stimulation of NCX activity can predispose VMs to Ca2+ overload under conditions where no significant changes in excitation-contraction coupling are yet evident.
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影响因子：
9.5
作者：
Ramirez, Rafael J.;Sah, Rajan;Backx, Peter H.
通讯作者：
Backx, Peter H.
影响因子：
5
作者：
DeSantiago J;Bare DJ;Semenov I;Minshall RD;Geenen DL;Wolska BM;Banach K
通讯作者：
Banach K
影响因子：
56.9
作者：
Prosser, Benjamin L.;Ward, Christopher W.;Lederer, W. J.
通讯作者：
Lederer, W. J.
DOI：
10.1152/ajpheart.00874.2003
发表时间：
2004-10-01
影响因子：
4.8
作者：
Eigel, BN;Gursahani, H;Hadley, RW
通讯作者：
Hadley, RW
影响因子：
20.1
作者：
Pott, C;Philipson, KD;Goldhaber, JI
通讯作者：
Goldhaber, JI