Arsenic trioxide induces unfolded protein response in vascular endothelial cells

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 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.

Tetramethylpyrazine (TMP) protects against sodium arsenite-induced nephrotoxicity by suppressing ROS production, mitochondrial dysfunction, pro-inflammatory signaling pathways and programed cell death

“…Recently, a role of ROS as the inducer of autophagy has been reported (Lee et al 2012). Meanwhile, our current findings were consistent with previous consensus that arsenic-induced cytotoxic effects were ROS-dependent (Weng et al 2013; Srivastava et al 2013; Kumagai and Sumi 2007). It has been demonstrated that GSH depletion was deeply involved in arsenic-induced ROS production (Yu et al 2013; Thompson and Franklin 2010).…”

Oral exposure of mice to cadmium (II), chromium (VI) and their mixture induce oxidative- and endoplasmic reticulum-stress mediated apoptosis in the livers

“…ER stress is provoked by the accumulation of unfolded or misfolded proteins in the ER lumen as a result of an imbalance between the load and capacity of protein folding (Ron and Walter, ; Pan et al, ). Increasing evidence has also revealed a direct connection between the production of ROS and ER stress (Malhotra and Kaufman, ; Weng et al, ). Generally, when ER stress occurred, some molecules such as GRP78, ATF6 would increase significantly (Lee, ; Pan et al, ).…”

Role of endoplasmic reticulum stress in drug‐induced toxicity

“…2015), or by the mitochondrial‐targeted antioxidant tiron (Weng et al. 2014). Since arsenic trioxide has been shown to increase mitochondrial ROS production possibly via an impairment of the respiratory chain (Paul et al.…”