Arsenic trioxide induces unfolded protein response in vascular endothelial cells

doi:10.1007/s00204-013-1101-x

CNU IR > Pharmacy and Science > Dept. of Biotechnology (including master's program) > Periodical Articles > Item 310902800/28510

Please use this identifier to cite or link to this item: https://ir.cnu.edu.tw/handle/310902800/28510

Title:	Arsenic trioxide induces unfolded protein response in vascular endothelial cells
Authors:	Weng, Ching-Yi Chiou, Shu-Yuan Wang, Lisu Kou, Mei-Chun Wang, Ying-Jan Wu, Ming-Jiuan
Contributors:	生物科技系食品科技系
Keywords:	Arsenic UPR ER stress ATF4 ATF6 Endothelial cells
Date:	2014-02
Issue Date:	2015-05-06 21:18:53 (UTC+8)
Publisher:	Springer Heidelberg
Abstract:	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.
Relation:	Archives of Toxicology, v.88 n.2, pp.213-226
Appears in Collections:	[Dept. of Food Science & Technology] Periodical Articles [Dept. of Biotechnology (including master's program)] Periodical Articles

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