期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 67, 期 -, 页码 77-85出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2013.12.017
关键词
p21-Activated kinase 1; Excitation-contraction coupling; Sodium calcium exchanger; Ischemia; Arrhythmia; Cardiomyocyte
资金
- National Institutes of Health [HL089617, HL089617-03S1, HL64035, HL062426, HL083218, HL083218-01A2S1]
- Campus Research Board Grant [S06-118]
- University of Illinois at Chicago
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 Pakl dependent increase in ROS was attenuated in VMs deficient for NADPH oxidase 2 (NOX2; p47(Phox-/-)) 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 Pakl 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. (C) 2013 Elsevier Ltd. All rights reserved.
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