Arsenite inhibits tissue-type plasminogen activator synthesis through NRF2 activation in cultured human vascular endothelial ea.Hy926 cells

Tsuyoshi Nakano, Tsutomu Takahashi, Chika Yamamoto, Eiko Yoshida, Toshiyuki Kaji, Yasuyuki Fujiwara

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number739
Pages (from-to)1-16
Number of pages16
JournalInternational journal of molecular sciences
Volume22
Issue number2
DOIs
Publication statusPublished - 2 Jan 2021

Keywords

  • Arsenite
  • Atherosclerosis
  • Endothelial cell
  • Fibrinolysis
  • Nuclear factor erythroid 2 related factor 2
  • Tissue-type plasminogen activator

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