Mitochondrial uncoupling, with low concentration FCCP, induces ROS-dependent cardioprotection independent of KATP channel activation
Mitochondrial uncoupling, with low concentration FCCP, induces ROS-dependent cardioprotection independent of KATP channel activation
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DOI：
10.1016/j.cardiores.2006.07.019
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发表时间：
2006-11-01
影响因子：
10.8
通讯作者：
Shattock, Michael J.
中科院分区：
文献类型：
--
作者：
Brennan, Jonathan P.;Southworth, Richard;Shattock, Michael J.
目的：K-ATP通道开放药物和缺血预处理均通过作用于线粒体内膜的K-ATP通道，解除质子梯度的偶联，部分消散线粒体膜电位，从而保护缺血心脏。这些研究的目的是使用低浓度的FCCP，线粒体质子载体，绕过线粒体K-ATP通道和部分解偶联的线粒体，并建立是否激活保护途径内的大鼠心脏类似于K-ATP通道开放剂或preconditioning.Methods：隔离，Langendorff灌注大鼠心脏进行25分钟的全球零流量缺血和功能恢复评估。在存在或不存在格列本脲（1 μ M）、5-羟基癸酸酯（5-HD：100 μ M）、N-乙酰半胱氨酸（4 mM）或N-2-巯基丙酰甘氨酸（1 mM）的情况下，用FCCP（30-300 nM）预处理心脏。结果：FCCP具有剂量依赖性的心肌保护作用，以100 nM FCCP为最佳浓度。这种作用不能被格列本脲或5-HD阻断，但可被N-乙酰半胱氨酸和N-2-巯基丙酰甘氨酸完全减弱。灌注FCCP（100 nM）没有耗尽散装ATP在预处理期间，但显着耗尽磷酸肌酸。在心室肌细胞中，FCCP引起的抗氧化剂敏感的增加ROS生产，但二氮嗪是没有effect.Conclusions：在离体大鼠心脏，部分线粒体解偶联与低剂量FCCP显着提高缺血后的功能恢复通过ROS依赖的途径。这种心脏保护作用不是通过细胞ATP耗竭或线粒体K-ATP通道激活介导的。(c)2006年欧洲心脏病学会。Elsevier B. V.出版，保留所有权利。
Objective: Both K-ATP channel opening drugs and ischaemic preconditioning have been suggested to protect the ischaemic heart by acting on K-ATP channels in the inner mitochondrial membrane, uncoupling the proton gradient and partially dissipating the mitochondrial membrane potential. The aim of these studies was to use low concentrations of FCCP, a mitochondrial protonophore, to bypass the mitochondrial K-ATP channel and partially uncouple the mitochondria and establish whether this activates protective pathways within the rat heart analogous to K-ATP channel openers or preconditioning.Methods: Isolated, Langendorff-perfused rat hearts were subjected to 25 min global zero-flow ischaemia and functional recovery assessed. Hearts were pretreated with FCCP (30-300 nM) in the presence or absence of glibenclamide (1 mu M), 5-hydroxydecanoate (5-HD: 100 mu M), N-acetyl cysteine (4 mM), or N-2-mercaptopropionyl glycine (1 mM). The metabolic consequences of FCCP perfusion in isolated hearts were studied using P-31 NMR, and reactive oxygen species (ROS) production was measured using DCF fluorescence in isolated rat ventricular myocytes.Results: FCCP exerted a dose-dependent cardioprotective effect, with 100 nM FCCP being the optimal concentration. This effect could not be blocked by glibenclamide or 5-HD, but was completely attenuated by N-acetyl cysteine and N-2-mercaptopropionyl glycine. Perfusion with FCCP (100 nM) did not deplete bulk ATP during the pretreatment period but significantly depleted phosphocreatine. In ventricular myocytes, FCCP caused an antioxidant-sensitive increase in ROS production but diazoxide was without effect.Conclusions: In the isolated rat heart, partial mitochondrial uncoupling with low-dose FCCP significantly improves post-ischaemic functional recovery via a ROS-dependent pathway. This cardioprotection is not mediated via the depletion of cellular ATP or mitochondrial K-ATP channel activation. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.