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Arsenite Inhibits Tissue-Type Plasminogen Activator Synthesis through NRF2 Activation in Cultured Human Vascular
Tsuyoshi Nakano1, Tsutomu Takahashi1, Chika Yamamoto2
1Department of Environmental Health, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji 192-0392, Japan.
Abstract:
Chronic arsenic exposure is known to be related to the progression of atherosclerosis. However, the pathogenic mechanisms of arsenic-induced atherosclerosis have not been fully elucidated. Because disruption of the blood coagulation/fibrinolytic system is involved in the development of arteriosclerosis, we investigated the effect of arsenite on fibrinolytic activity in human vascular endothelial EA.hy926 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 reduced fibrinolytic t-PA activity by inhibiting its synthesis without affecting PAI-1 production. The inhibitory effect of arsenite on t-PA expression was partially recovered by the reactive oxygen species (ROS) scavenger Trolox. The nuclear factor erythroid 2 related factor 2 (NRF2) pathway is known to be activated by arsenite via ROS production. We confirmed that arsenite activated the NRF2 pathway, and arsenite-induced inhibition of fibrinolytic t-PA activity was abrogated in NRF2-knockdown EA.hy926 cells. These results suggest that arsenite inhibits the fibrinolytic activity of t-PA by selectively suppressing its synthesis via activation of the NRF2 pathway in vascular endothelial cells.
Insights
Chronic arsenic exposure impairs blood vessel function by reducing fibrinolysis. Arsenite inhibits tissue-type plasminogen activator (t-PA) synthesis via the NRF2 pathway, contributing to atherosclerosis progression.
Area of Science:
- Toxicology
- Cardiovascular Biology
- Cell Biology
Background:
- Chronic arsenic exposure is linked to atherosclerosis progression.
- The precise mechanisms of arsenic-induced atherosclerosis remain unclear.
- Disruption of the blood coagulation/fibrinolytic system contributes to arteriosclerosis.
Purpose of the Study:
- To investigate the impact of arsenite on fibrinolytic activity in human vascular endothelial cells.
- To elucidate the role of the tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) balance in arsenite's effects.
- To determine the involvement of the Nuclear Factor erythroid 2 related factor 2 (NRF2) pathway.
Main Methods:
- Cultured human vascular endothelial EA.hy926 cells were treated with arsenite.
- Fibrinolytic activity, t-PA, and PAI-1 levels were measured.
- The effects of reactive oxygen species (ROS) scavenger Trolox and NRF2-knockdown were assessed.
Main Results:
- Arsenite significantly reduced fibrinolytic t-PA activity by inhibiting its synthesis, without affecting PAI-1 production.
- The inhibitory effect of arsenite on t-PA expression was partially reversed by Trolox.
- Arsenite activated the NRF2 pathway, and NRF2 knockdown abrogated the inhibition of t-PA activity.
Conclusions:
- Arsenite inhibits the fibrinolytic activity of t-PA through selective suppression of its synthesis.
- The NRF2 pathway, activated by arsenite via ROS, mediates the inhibition of t-PA synthesis.
- These findings highlight a novel mechanism in arsenic-induced vascular dysfunction and atherosclerosis.
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