Mitochondrial reactive oxygen species: which ROS signals cardioprotection?
Mitochondrial reactive oxygen species: which ROS signals cardioprotection?
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DOI：
10.1152/ajpheart.00858.2012
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发表时间：
2013-10-01
影响因子：
4.8
通讯作者：
Garlid, Keith D.
中科院分区：
文献类型：
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作者：
Garlid, Anders O.;Jaburek, Martin;Garlid, Keith D.
线粒体是通过开放线粒体ATP敏感性钾通道（mitoK（ATP））的程序（包括缺血预处理和药物预处理）的心脏保护的主要效应器。MitoK（ATP）开放导致活性氧物质（ROS）增加，其然后激活mitoK（ATP）相关的PKC β，其磷酸化mitoK（ATP）并使其处于持续开放状态（Costa AD，Garlid KD. Am J Physiol Heart Circ Physiol 295，H874-H882，2008）。造成这种效应的ROS尚不清楚。本研究的重点是超氧化物（O-2（中心点-）），过氧化氢（H2 O2），和羟基自由基（HO中心点），其中每一个已被提出作为信号活性氧。mitoK（ATP）的反馈激活为研究内源性ROS信号提供了理想的环境。呼吸的大鼠心脏线粒体与ATP和二氮嗪，连同正在测试的代理人干扰这一过程中，无论是清除活性氧或通过阻断活性氧转化预孵育。然后测定线粒体以确定是否达到持续的磷酸化开放状态。二甲基亚砜（DMSO），二甲基甲酰胺（DMF），去铁胺，Trolox，和溴烯醇内酯的ROS依赖性开放状态的形成干扰。过氧化氢酶不干扰该步骤。我们还发现DMF阻断了缺血预处理和二氮嗪的心脏保护作用。缺乏过氧化氢酶作用和作用于HO中心点下游的试剂的抑制作用排除了H2 O2作为内源性信号传导ROS。综上所述，这些结果支持ROS信息由HO中心点的下游产物携带的结论，并且它可能是磷脂氧化的产物。
Mitochondria are the major effectors of cardioprotection by procedures that open the mitochondrial ATP-sensitive potassium channel (mitoK(ATP)), including ischemic and pharmacological preconditioning. MitoK(ATP) opening leads to increased reactive oxygen species (ROS), which then activate a mitoK(ATP)-associated PKC epsilon, which phosphorylates mitoK(ATP) and leaves it in a persistent open state (Costa AD, Garlid KD. Am J Physiol Heart Circ Physiol 295, H874-H882, 2008). The ROS responsible for this effect is not known. The present study focuses on superoxide (O-2(center dot-)), hydrogen peroxide (H2O2), and hydroxyl radical (HO center dot), each of which has been proposed as the signaling ROS. Feedback activation of mitoK(ATP) provides an ideal setting for studying endogenous ROS signaling. Respiring rat heart mitochondria were preincubated with ATP and diazoxide, together with an agent being tested for interference with this process, either by scavenging ROS or by blocking ROS transformations. The mitochondria were then assayed to determine whether or not the persistent phosphorylated open state was achieved. Dimethylsulfoxide (DMSO), dimethylformamide (DMF), deferoxamine, Trolox, and bromoenol lactone each interfered with formation of the ROS-dependent open state. Catalase did not interfere with this step. We also found that DMF blocked cardioprotection by both ischemic preconditioning and diazoxide. The lack of a catalase effect and the inhibitory effects of agents acting downstream of HO center dot excludes H2O2 as the endogenous signaling ROS. Taken together, the results support the conclusion that the ROS message is carried by a downstream product of HO center dot and that it is probably a product of phospholipid oxidation.