Mitochondrial instability during regional ischemia-reperfusion underlies arrhythmias in monolayers of cardiomyocytes.
Mitochondrial instability during regional ischemia-reperfusion underlies arrhythmias in monolayers of cardiomyocytes.
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DOI：
10.1016/j.yjmcc.2014.09.024
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发表时间：
2015-01
影响因子：
5
通讯作者：
O'Rourke, Brian
中科院分区：
文献类型：
--
作者：
Solhjoo, Soroosh;O'Rourke, Brian
关键词：
线粒体网络的局部去极化可以改变细胞的电兴奋性，增加再入的倾向，部分是通过打开肌层的KATP通道。线粒体内膜电位（ΔΨm）不稳定或振荡可通过暴露于活性氧（ROS）、激光激发或谷胱甘肽耗竭而在肌细胞中诱导，并且被认为是缺血-再灌注期间心律失常的主要因素。然而，ΔΨm恢复动力学和再灌注引起的心律失常之间的相关性很难通过实验证明。在这里，我们研究了新生大鼠心室肌细胞（NRVM）单层覆盖诱导的缺血-再灌注（IR）过程中ΔΨm亚细胞变化、细胞谷胱甘肽氧化还原电位、电兴奋性和波传播之间的关系。缺血导致动作电位幅度和持续时间下降，缺血约15 min后出现电性不兴奋。ΔΨm去极化发生在缺血的两个阶段：在第1阶段（缺血< 30分钟），单个nrvm内的线粒体团团去极化，而第2阶段ΔΨm去极化（30 - 60分钟）的特征是线粒体网络在整个单层缺血区域的整体功能崩溃，通常涉及代谢波的传播。谷胱甘肽（GSSG:GSH）氧化还原电位发生在缺血期间，随后在再灌注时恢复（即打开盖子）。ΔΨm在再灌注后很快在单个肌细胞的线粒体中恢复（< 5分钟），但高度不稳定，其特征是在再灌注区nrvm中出现亚细胞振荡或线粒体簇的闪烁。电兴奋性也以不均匀的方式恢复，提供致心律失常的底物，导致形成持续的再入。4′-氯地西泮（一种外周苯二氮卓受体配体）治疗可防止ΔΨm振荡，提高GSH恢复率，并防止再灌注时再进入，表明线粒体网络动力学的稳定是预防缺血性心律失常的重要组成部分。
Regional depolarization of the mitochondrial network can alter cellular electrical excitability and increase the propensity for reentry, in part, through the opening of sarcolemmal KATP channels. Mitochondrial inner membrane potential (ΔΨm) instability or oscillation can be induced in myocytes by exposure to reactive oxygen species (ROS), laser excitation, or glutathione depletion, and is thought to be a major factor in arrhythmogenesis during ischemia-reperfusion. Nevertheless, the correlation between ΔΨm recovery kinetics and reperfusion-induced arrhythmias has been difficult to demonstrate experimentally. Here, we investigate the relationship between subcellular changes in ΔΨm, cellular glutathione redox potential, electrical excitability, and wave propagation during coverslip-induced ischemia-reperfusion (IR) in neonatal rat ventricular myocyte (NRVM) monolayers. Ischemia led to decreased action potential amplitude and duration followed by electrical inexcitability after ~ 15 min of ischemia. ΔΨm depolarization occurred in two phases during ischemia: in phase 1 (< 30 min ischemia), mitochondrial clusters within individual NRVMs depolarized, while phase 2 ΔΨm depolarization (30–60 min) was characterized by global functional collapse of the mitochondrial network across the whole ischemic region of the monolayer, typically involving a propagating metabolic wave. Oxidation of the glutathione (GSSG:GSH) redox potential occurred during ischemia, followed by recovery upon reperfusion (i.e., lifting the coverslip). ΔΨm recovered in the mitochondria of individual myocytes quite rapidly upon reperfusion (< 5 min), but was highly unstable, characterized by subcellular oscillations or flickering of clusters of mitochondria in NRVMs across the reperfused region. Electrical excitability also recovered in a heterogeneous manner, providing an arrhythmogenic substrate which led to formation of sustained reentry. Treatment with 4′-chlorodiazepam, a peripheral benzodiazepine receptor ligand, prevented ΔΨm oscillation, improved GSH recovery rate, and prevented reentry during reperfusion, indicating that stabilization of mitochondrial network dynamics is an important component of preventing post-ischemic arrhythmias.
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谷胱甘肽氧化诱导的心律不齐可以通过预防线粒体去极化来抑制。
影响因子：
5
作者：
Brown, David A.;Aon, Miguel A.;Frasier, Chad R.;Sloan, Ruben C.;Maloney, Andrew H.;Anderson, Ethan J.;O'Rourke, Brian
通讯作者：
O'Rourke, Brian
影响因子：
20.1
作者：
Kassiri, Z;Zobel, C;Backx, PH
通讯作者：
Backx, PH
DOI：
10.1073/pnas.0307156101
发表时间：
2004-03-30
影响因子：
11.1
作者：
Aon, MA;Cortassa, S;O'Rourke, B
通讯作者：
O'Rourke, B
影响因子：
20.1
作者：
Akao, M;Ohler, A;Marbán, E
通讯作者：
Marbán, E
影响因子：
37.8
作者：
Go, Alan S.;Mozaffarian, Dariush;Turner, Melanie B.
通讯作者：
Turner, Melanie B.