Arsenic trioxide induces growth inhibition and death in human pulmonary artery smooth muscle cells accompanied by mitochondrial O2•- increase and GSH depletion
Arsenic trioxide induces growth inhibition and death in human pulmonary artery smooth muscle cells accompanied by mitochondrial O2•- increase and GSH depletion
复制标题
DOI：
10.1002/tox.22569
复制
发表时间：
2018-08-01
影响因子：
4.5
通讯作者：
Kim, Sung Zoo
中科院分区：
文献类型：
--
作者：
Park, Woo Hyun;Han, Bo Ran;Kim, Sung Zoo
三氧化二砷（ATO; As 2 O3）通过氧化应激诱导各种细胞的细胞死亡。慢性砷暴露与血管疾病的发展有关。然而，很少有人知道ATO对人正常血管平滑肌细胞（VSMCs）的细胞毒性作用。因此，在这项研究中，我们研究了ATO对人肺动脉平滑肌（HPASM）细胞的细胞生长和死亡的影响与活性氧（ROS）和谷胱甘肽（GSH）水平的关系。ATO处理24 h可抑制HPASM细胞的生长，其IC_（50）约为30-50 M，ATO可诱导HPASM细胞凋亡或坏死，并与剂量有关。用50 M ATO处理在早期时间点没有增加ROS水平，但在24 h时显著增加线粒体O2（中心点-）水平。ATO还诱导HPASM细胞中GSH耗竭。N-乙酰半胱氨酸（NAC;一种众所周知的抗氧化剂）并不显著影响ATO处理的HPASM细胞中的凋亡性细胞死亡、ROS水平或GSH消耗。然而，l-丁硫基乙砜亚胺（BSO; GSH合成的抑制剂）增强ATO处理的HPASM细胞中线粒体O2（中心点-）水平，并显著增加这些细胞中的细胞死亡和GSH耗竭。总之，我们提供了第一个证据表明ATO抑制HPASM细胞的生长，并诱导这些细胞的凋亡和/或坏死性细胞死亡，伴随着线粒体O2（中心点-）水平的增加和GSH耗竭。
Arsenic trioxide (ATO; As2O3) induces cell death in various cells via oxidative stress. Expose to chronic arsenic is involved in the development of vascular diseases. However, little is known about the cytotoxic effects of ATO on human normal vascular smooth muscle cells (VSMCs). Thus, in this study, we investigated the effects of ATO on cell growth and death in human pulmonary artery smooth muscle (HPASM) cells in relation to reactive oxygen species (ROS) and glutathione (GSH) levels. ATO treatment decreased the growth of HPASM cells with an IC50 of approximate to 30-50 M at 24 h, and ATO induced HPASM cell death via apoptosis or necrosis dependent on the doses of it at this time. Treatment with 50 M ATO did not increase ROS levels at the early time points, but it significantly increased mitochondrial O2(center dot-) levels at 24 h. ATO also induced GSH depletion in HPASM cells. N-acetyl cysteine (NAC; a well-known antioxidant) did not significantly affect apoptotic cell death, ROS levels, or GSH depletion in ATO-treated HPASM cells. However, l-buthionine sulfoximine (BSO; an inhibitor of GSH synthesis) intensified mitochondrial O2(center dot-) levels in ATO-treated HPASM cells, and significantly increased cell death and GSH depletion in these cells as well. In summary, we provided the first evidence that ATO inhibited the growth of HPASM cells, and induced apoptotic and/or necrotic cell death in these cells, accompanied by increases in mitochondrial O2(center dot-) level and GSH depletion.