Toxic mechanisms of arsenite on the blood coagulation/fibrinolytic system

<p> Epidemiological studies and animal experiments have shown that chronic arsenic exposure is known to be related to the development and progression of vascular lesions, including atherosclerosis. However, the mechanism of pathogenesis remains largely unknown. Since disruption of the blood coagulation/fibrinolytic system is involved in the development of arteriosclerosis. Therefore, we first investigated the effect of arsenite on fibrinolytic activity in human vascular endothelial cells in the present study. Fibrinolysis depends on the balance between tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) secreted from vascular endothelial cells. We found that arsenite inhibits the fibrinolytic activity of t-PA by selectively suppressing its synthesis via activation of the Nrf2 pathway in vascular endothelial cells. Also, we found that arsenite stimulates the expression of tissue factor (TF), which is the initiator of the coagulation, via activation of the Nrf2 pathway in both human aortic smooth muscle cells and macrophage-like human THP-1 cells. These results suggest that arsenite causes a disruption of the blood coagulation/fibrinolytic system via activation of the Nrf2 pathway in vascular component cells.</p>