Volume-sensitive chloride channels (ICl,vol) mediate doxorubicin-induced apoptosis through apoptotic volume decrease in cardiomyocytes
Volume-sensitive chloride channels (ICl,vol) mediate doxorubicin-induced apoptosis through apoptotic volume decrease in cardiomyocytes
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DOI：
10.1111/j.1472-8206.2004.00273.x
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发表时间：
2004-10-01
影响因子：
2.9
通讯作者：
Berdeaux, A
中科院分区：
文献类型：
--
作者：
de Tassigny, AD;Souktani, R;Berdeaux, A
细胞凋亡与细胞体积的早期变化有关，其机制称为细胞凋亡体积减少（AVD）。由于容量敏感性氯通道（I-C1，I-vol）在细胞体积调节中起关键作用，本研究探讨了I-C1，I-vol和AVD在阿霉素诱导的成年兔心室肌细胞凋亡中的作用。心肌细胞暴露于1 μ m阿霉素诱导心肌细胞的细胞体积快速和显着减少（平均15%），即AVD以及细胞凋亡，膜联蛋白V标记和caspase-3活性的早期标志物的增加。阿霉素也诱导激活的电流特征为I-C1，I-vol的基础上的外部氯敏感性和药理学性质与膜片钳技术。当心肌细胞暴露于I-C1，I-vol抑制剂5-硝基-2-（3-苯基丙基氨基）苯甲酸（NPPB）（0.1 μ m）或茚满基氧基乙酸94（IAA-94）（10 μ m）时，多柔比星诱导的AVD和凋亡均被废除。使用另一种促凋亡化合物C-2-神经酰胺证实了I-C1、I-vol在AVD和凋亡过程中的关键作用。这些结果表明，I-C1，I-vol的激活在导致细胞收缩和凋亡诱导的AVD的机制中起着重要作用，该机制由药物如阿霉素或C-2-神经酰胺在成年心肌细胞中引起。
Apoptosis is associated with early changes in cell volume through a mechanism called apoptotic volume decrease (AVD). As volume-sensitive chloride channels (I-C1,I-vol) are known to play a key role in the regulation of cell volume, this study investigated the role of I-C1,I-vol and AVD in doxorubicin-induced apoptotic cell death in adult rabbit ventricular cardiomyocytes. Exposure of cardiomyocytes to 1 mum doxorubicin induced a rapid and significant reduction in cell volume of cardiomyocytes (average of 15%), i.e. AVD as well as increases in the early markers of apoptosis, annexin V labeling and caspase-3 activity. Doxorubicin also induced the activation of a current characterized as I-C1,I-vol on the basis of the external chloride sensitivity and pharmacological properties with the patch clamp technique. Doxorubicin-induced AVD and apoptosis were both abolished when cardiomyocytes were exposed to the I-C1,I-vol inhibitors 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) (0.1 mm) or indanyloxyacetic acid 94 (IAA-94) (10 mum). The crucial role of I-C1,I-vol during AVD and apoptosis was confirmed using C-2-ceramide, another pro-apoptotic compound. These results demonstrate that activation of I-C1,I-vol plays a major role in the mechanism leading to cell shrinkage and apoptosis-induced AVD by agents such as doxorubicin or C-2-ceramide in adult cardiomyocytes.