Arsenic trioxide induces unfolded protein response in vascular endothelial cells

Ching Yi Weng, Shu Yuan Chiou, Lisu Wang, Mei Chun Kou, Ying-Jan Wang, Ming Jiuan Wu

Research output: Contribution to journalArticle

23 Citations (Scopus)

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 As 2O3 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.

Original languageEnglish
Pages (from-to)213-226
Number of pages14
JournalArchives of Toxicology
Volume88
Issue number2
DOIs
Publication statusPublished - 2014 Feb 1

Fingerprint

Unfolded Protein Response
Endothelial cells
Arsenic
Endothelial Cells
Prokaryotic Initiation Factor-2
1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt
Transcription Factor CHOP
Eukaryotic Initiation Factor-2
Eukaryotic Initiation Factors
Proteins
Endoplasmic Reticulum Stress
Cytotoxicity
Thioctic Acid
Apoptosis
Neutral Amino Acid Transport Systems
Genes
Chemical activation
arsenic trioxide
Calcium
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Weng, Ching Yi ; Chiou, Shu Yuan ; Wang, Lisu ; Kou, Mei Chun ; Wang, Ying-Jan ; Wu, Ming Jiuan. / Arsenic trioxide induces unfolded protein response in vascular endothelial cells. In: Archives of Toxicology. 2014 ; Vol. 88, No. 2. pp. 213-226.
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Arsenic trioxide induces unfolded protein response in vascular endothelial cells. / Weng, Ching Yi; Chiou, Shu Yuan; Wang, Lisu; Kou, Mei Chun; Wang, Ying-Jan; Wu, Ming Jiuan.

In: Archives of Toxicology, Vol. 88, No. 2, 01.02.2014, p. 213-226.

Research output: Contribution to journalArticle

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