Molecular mechanism for arsenite-mediated dysfunction of blood-coagulation systems in human vascular endothelial cells and smooth muscle cells

<p>The chronic arsenic exposure is known to be related to the progression of atherosclerosis, although the pathogenic mechanisms are not fully elucidated. One of the risk factors for atherosclerosis is disruption of the blood coagulation-fibrinolysis system regulated by vascular component cells, such as vascular endothelial cells and smooth muscle cells. We previously reported that arsenite suppress the fibrinolytic activity of the vascular endothelial cells through selective inhibition of the expression of t-PA via activation of Nrf2. On the other hand, effect of arsenite on expression of genes involved in blood coagulation system was not fully elucidated. In this study, we investigated the effect of arsenite on expression of genes involved in blood coagulation and anticoagulation system in vascular endothelial cells and smooth muscle cells. We obtained the following results. </p><p>(1) Arsenite suppressed expression of thrombomodulin (TM), an anticoagulation factor, in vascular endothelial cells. </p><p>(2) Arsenite upregulated expression of tissue factor (TF), a coagulation initiator, in vascular smooth muscle cells. </p><p>(3) Suppression of TM by arsenite was recovered by siRNA-mediated knockdown of Nrf2 in vascular endothelial cells.</p><p>(4) Induction of TF by arsenite was suppressed by siRNA-mediated knockdown of Nrf2 in vascular smooth muscle cells.</p><p>These results suggest that arsenite induces a procoagulant state of blood to progress atherosclerosis through suppression of TM and induction of TF expression via Nrf2 pathway activation in vascular component cells.</p>