Abstract
Exposure to arsenic exacerbates atherosclerosis, however, mechanisms of atherogenic affects of arsenic are not known. In the present study, we show that exposure of endothelial cells (EC) to arsenic significantly (P<0.01) increased the expression of IL‐8, permeability of endothelial cell monolayer and transmigration of leukocytes. Arsenic also increased the expression of ER‐resident chaperones ‐ GRP78, GRP94 and HERP by 1.4–5.4‐fold. Moreover, arsenic, induced the phosphorylation of eIF2á, and the expression of its downstream transcription factors such as ATF3 and CHOP by 2–6‐fold. Exposure to arsenic also led to the splicing of the bZIP transcription factor, XBP‐1. Adenoviral transfection of EC with ATF‐6 increased the expression of several ER chaperones and inhibited the arsenic‐induced IL‐8 expression and transmigration of leukocytes by >50 %. Anti‐IL‐8 antibody and antagonist of IL‐8 receptor (CXCR‐2), SB225002, also significantly (P<0.01) inhibited the arsenic‐induced transmigration of leukocytes. These data suggest that arsenic‐induced cytokine production can increase endothelial activation and leukocytes transmigration in a ER‐stress dependent manner. ER‐stress therefore, could be an important regulator of endothelial activation and atherogenesis.
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