Archives of Toxicology

, Volume 88, Issue 2, pp 213–226 | Cite as

Arsenic trioxide induces unfolded protein response in vascular endothelial cells

  • Ching-Yi Weng
  • Shu-Yuan Chiou
  • Lisu Wang
  • Mei-Chun Kou
  • Ying-Jan WangEmail author
  • Ming-Jiuan WuEmail author
Inorganic Compounds


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 α-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 α (eIF2α), 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 eIF2α, 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 eIF2α 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.


Arsenic UPR ER stress ATF4 ATF6 Endothelial cells 



This study was supported by Grant NSC-99-2320-B-041-005-MY3 (to M.-J. Wu) from National Science Council, Taiwan, ROC.

Supplementary material

204_2013_1101_MOESM1_ESM.doc (79 kb)
Supplementary material 1 (DOC 79 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Department of BiotechnologyChia Nan University of Pharmacy and ScienceTainanTaiwan
  2. 2.Crop Improvement SectionHualien District Agricultural Research and Extension StationHualienTaiwan
  3. 3.Department of Food Science and TechnologyChia Nan University of Pharmacy and ScienceTainanTaiwan
  4. 4.Department of Environmental and Occupational HealthNational Cheng Kung University Medical CollegeTainanTaiwan
  5. 5.Sustainable Environment Research CentreNational Cheng Kung UniversityTainanTaiwan

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