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| 標題: | Arsenic trioxide induces unfolded protein response in vascular endothelial cells |
| 作者: | Weng, Ching-Yi
Chiou, Shu-Yuan
Wang, Lisu
Kou, Mei-Chun
Wang, Ying-Jan
Wu, Ming-Jiuan |
| 貢獻者: | 生物科技系
食品科技系 |
| 關鍵字: | Arsenic
UPR
ER stress
ATF4
ATF6
Endothelial cells |
| 日期: | 2014-02 |
| 上傳時間: | 2015-05-06 21:18:53 (UTC+8) |
| 出版者: | Springer Heidelberg |
| 摘要: | Chronic arsenic exposure has been linked to endothelial dysfunction and apoptosis. We investigate the involvement of unfolded protein response (UPR) signaling in the arsenic-mediated cytotoxicity of the SVEC4-10 mouse endothelial cells. The SVEC4-10 cells underwent apoptosis in response to As2O3 dose- and time-dependently, accompanied by increased accumulation of calcium, and activation of caspase-3. These phenomena were completely inhibited by alpha-lipoic acid (LA), which did not scavenge ROS over-production, but were only partially or not ameliorated by tiron, a potent superoxide scavenger. Moreover, arsenic activated UPR, leading to phosphorylation of eukaryotic translation initiation factor 2 subunit alpha (eIF2 alpha), induction of ATF4, and processing of ATF6. Treatment with arsenic also triggered the expression of endoplasmic reticulum (ER) stress markers, GRP78 (glucose-regulated protein), and CHOP (C/EBP homologous protein). The activation of eIF2 alpha, ATF4 and ATF6 and expression of GRP78 and CHOP are repressed by both LA and tiron, indicating arsenic-induced UPR is mediated through ROS-dependent and ROS-independent pathways. Arsenic also induced ER stress-inducible genes, BAX, PUMA (p53 upregulated modulator of apoptosis), TRB3 (tribbles-related protein 3), and SNAT2 (sodium-dependent neutral amino acid transporter 2). Consistent with intracellular calcium and cell viability data, ROS may not be important in arsenic-induced death, because tiron did not affect the expression of these pro-apoptotic genes. In addition, pretreatment with salubrinal, a selective inhibitor of eIF2 alpha dephosphorylation, enhanced arsenic-induced GRP78 and CHOP expression and partially prevented arsenic cytotoxicity in SVEC4-10 cells. Taken together, these results suggest that arsenic-induced endothelial cytotoxicity is associated with ER stress, which is mediated by ROS-dependent and ROS-independent signaling. |
| 關聯: | Archives of Toxicology, v.88 n.2, pp.213-226 |
| 顯示於類別: | [ 食品科技系 ] 期刊論文
[生物科技系(所)] 期刊論文
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