Cardiac arrhythmias induced by glutathione oxidation can be inhibited by preventing mitochondrial depolarization.
Cardiac arrhythmias induced by glutathione oxidation can be inhibited by preventing mitochondrial depolarization.
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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。
DOI：
10.1016/j.yjmcc.2009.11.011
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发表时间：
2010-04
影响因子：
5
通讯作者：
O'Rourke, Brian
中科院分区：
文献类型：
--
作者：
Brown, David A.;Aon, Miguel A.;Frasier, Chad R.;Sloan, Ruben C.;Maloney, Andrew H.;Anderson, Ethan J.;O'Rourke, Brian
关键词：
我们以前提出，在缺血和再灌注期间，线粒体内膜电位（Δ Δ m）的不均匀塌陷通过在心肌中形成代谢汇而有助于心肌发生，其中具有未偶联线粒体和高KATP电流水平的肌细胞簇改变电传播以促进折返。单个肌细胞研究还表明，通过活性氧（ROS）诱导的ROS释放机制，细胞范围内的Δ λ m去极化可由二酰胺（一种谷胱甘肽氧化剂）全面耗尽抗氧化剂库触发。在这里，我们研究是否二酰胺引起线粒体去极化，促进心律失常在常氧离体灌注豚鼠心脏。我们还研究了线粒体苯二氮卓类受体（4′-氯地西泮; 4-ClDzp）配体稳定Δ β m是否可以阻止代谢汇的形成，从而阻止心律失常。通过用200μM二酰胺处理35分钟，然后洗脱，启动GSH合并液的氧化。该处理增加了GSSG，降低了总GSH和GSH/GSSG比率。在联胺暴露期间，接受联胺的所有心脏均从窦性心律转变为室性心动过速和/或室颤：心律失常评分为5.5 ± 0.5; n=6个心脏。这些心律失常和受损的LV功能通过共同施用4-ClDzp（64μM）被显著抑制：联胺+ 4-ClDzp的心律失常评分为0.4± 0.2（n=5; P < 0.05，与单独的联胺相比）。完整心脏中的Δ λ m成像显示Δ λ m在20分钟内开始不均匀塌陷为二酰胺，与心律失常发作的时间范围平行。4-ClDzp治疗可防止Δ m的丢失，心肌GSSG的增加也是如此。这些研究结果表明，氧化应激诱导的氧化还原型谷胱甘肽与二酰胺可导致机电功能障碍，在常氧条件下。类似于缺血再灌注损伤，功能障碍取决于线粒体能量状态。靶向线粒体苯二氮卓受体可以预防氧化应激模型中的电和机械功能障碍。
We have previously proposed that the heterogeneous collapse of mitochondrial inner membrane potential (ΔΨm) during ischemia and reperfusion contributes to arrhythmogenesis through the formation of metabolic sinks in the myocardium, wherein clusters of myocytes with uncoupled mitochondria and high KATP current levels alter electrical propagation to promote reentry. Single myocyte studies have also shown that cell-wide ΔΨm depolarization, through a reactive oxygen species (ROS) -induced ROS release mechanism, can be triggered by global depletion of the antioxidant pool with diamide, a glutathione oxidant. Here we examine whether diamide causes mitochondrial depolarization and promotes arrhythmias in normoxic isolated perfused guinea pig hearts. We also investigate whether stabilization of ΔΨm with a ligand of the mitochondrial benzodiazepine receptor (4′-chlorodiazepam; 4-ClDzp) prevents the formation of metabolic sinks and, consequently, precludes arrhythmias. Oxidation of the GSH pool was initiated by treatment with 200μM diamide for 35 minutes, followed by washout. This treatment increased GSSG and decreased both total GSH and the GSH/GSSG ratio. All hearts receiving diamide transitioned from sinus rhythm into ventricular tachycardia and/or ventricular fibrillation during the diamide exposure: arrhythmia scores were 5.5 ± 0.5; n=6 hearts. These arrhythmias and impaired LV function were significantly inhibited by co-administration of 4-ClDzp (64μM): arrhythmia scores with diamide + 4-ClDzp were 0.4± 0.2 (n=5; P < 0.05 vs. diamide alone). Imaging ΔΨm in intact hearts revealed the heterogeneous collapse of ΔΨm beginning 20 minutes into diamide, paralleling the timeframe for the onset of arrhythmias. Loss of ΔΨm was prevented by 4-ClDzp treatment, as was the increase in myocardial GSSG. These findings show that oxidative stress induced by oxidation of GSH with diamide can cause electromechanical dysfunction under normoxic conditions. Analogous to ischemia-reperfusion injury, the dysfunction depends on the mitochondrial energy state. Targeting the mitochondrial benzodiazepine receptor can prevent electrical and mechanical dysfunction in both models of oxidative stress.
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影响因子：
4.8
作者：
Aon, Miguel A.;Cortassa, Sonia;O'Rourke, Brian
通讯作者：
O'Rourke, Brian
影响因子：
10.8
作者：
CURTIS, MJ;WALKER, MJA
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WALKER, MJA
影响因子：
7.4
作者：
KONYA, L;KEKESI, V;FEHER, J
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FEHER, J
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7.4
作者：
BINDOLI, A;CAVALLINI, L;DILISA, F
通讯作者：
DILISA, F
影响因子：
4.8
作者：
Aon, MA;Cortassa, S;O'Rourke, B
通讯作者：
O'Rourke, B