Mechanism of arsenite-induced expression of reactive sulfur species-prducing enzyme CSE in cultured vascular endothelial cells

Abstract

Arsenic is a toxic pollutant in environment. Chronic arsenic exposure is known to be related to the progression of atherosclerosis. The molecular mechanism underlying the development of arsenic toxicity include the inhibition of enzyme activity and increased production of reactive oxygen species (ROS). Recent reports indicate that reactive sulfur species (RSS) have protective effects against ROS. We have previously found that arsenite induces the expression of cystathionine gamma-lyase (CSE), a RSS-producing enzyme, in vascular endothelial cells. In this study, we investigated the involvement of induction of CSE expression in arsenite toxicity in vascular endothelial cells. We found that knockdown of CSE by siRNA enhances the sensitivity of vascular endothelial cells to arsenite. This suggests that CSE acts as a protective factor against arsenite-induced cytotoxicity. Nrf2, NF-κB, HIF-1, and ATF4 have been reported to be transcription factors involved in the regulation of CSE expression. Therefore, we investigated the involvement of these transcription factors in arsenite-induced CSE expression. siRNA-mediated knockdown of Nrf2 did not affect the induction of CSE expression, while NF-κB inhibitor (SC-514) conversely promoted the induction of CSE expression. On the other hand, siRNA-mediated knockdown of HIF-1 partially suppressed the induction of CSE expression by arsenite. These findings suggest that activation of the HIF-1 pathway is partially involved in the mechanism of CSE expression induction by arsenite. The involvement of ATF4 in this induction mechanism is currently under investigation.