Park Woo Hyun, Han Bo Ran, Park Hyun Kyung, Kim Sung Zoo
Department of Physiology, Medical School, Research Institute for Endocrine Sciences, Chonbuk National University, 20 Geonji-ro, Deokjin, Jeonju, Jeollabuk, 54907, Republic of Korea.
Environ Toxicol. 2018 Apr 30. doi: 10.1002/tox.22569.
Arsenic trioxide (ATO; As O ) 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 IC of ∼30-50 μM 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 μM ATO did not increase ROS levels at the early time points, but it significantly increased mitochondrial O2•- 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•- 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•- level and GSH depletion.
三氧化二砷（ATO；As₂O₃）通过氧化应激诱导多种细胞死亡。长期接触砷与血管疾病的发生有关。然而，关于ATO对人正常血管平滑肌细胞（VSMCs）的细胞毒性作用知之甚少。因此，在本研究中，我们研究了ATO对人肺动脉平滑肌（HPASM）细胞生长和死亡的影响，以及与活性氧（ROS）和谷胱甘肽（GSH）水平的关系。ATO处理在24小时时以约30 - 50 μM的半数抑制浓度（IC）降低了HPASM细胞的生长，此时ATO通过凋亡或坏死诱导HPASM细胞死亡，具体取决于其剂量。50 μM ATO处理在早期时间点并未增加ROS水平，但在24小时时显著增加了线粒体超氧阴离子（O₂•-）水平。ATO还诱导了HPASM细胞中的GSH消耗。N - 乙酰半胱氨酸（NAC；一种著名的抗氧化剂）对ATO处理的HPASM细胞中的凋亡细胞死亡、ROS水平或GSH消耗没有显著影响。然而，丁硫氨酸亚砜胺（BSO；一种GSH合成抑制剂）增强了ATO处理的HPASM细胞中的线粒体O₂•-水平，并显著增加了这些细胞中的细胞死亡和GSH消耗。总之，我们首次提供证据表明ATO抑制了HPASM细胞的生长，并在这些细胞中诱导了凋亡和/或坏死性细胞死亡，同时伴随着线粒体O₂•-水平的升高和GSH消耗。
