Disruption of blood coagulation and fibrinolysis system by arsenic and elucidation of its possible mechanisms.

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K12185
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 63030:Chemical substance influence on environment-related
• Research Institution: Tokyo University of Pharmacy and Life Science
• Principal Investigator: Fujiwara Yasuyuki 東京薬科大学, 薬学部, 教授 (40247482)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: ヒ素 / 血液凝固線溶系 / 血管内皮細胞 / 血管平滑筋細胞 / 血管周囲脂肪組織 / 動脈硬化

Outline of Final Research Achievements

In the present study, we have elucidated the mechanism by which arsenite selectively suppresses the production of tissue-type plasminogen activator (t-PA), a pro-fibrinolytic factor, via activation of the Nrf-2/ARE pathway in human vascular endothelial cells, resulting in a decrease in t-PA fibrinolytic activity in the liquid phase. We also found that arsenite increased the expression of PAI-1, an inhibitor of t-PA, and tissue factor (TF), a procoagulant factor, on vascular smooth muscle cells and macrophage-like cells. Furthermore, arsenite caused a decrease in the expression of t-PA in vascular tissues of mice, and also decreased the amount of t-PA in the serum. This suggests that arsenite inhibits fibrinolytic activity through suppressing the expression of fibrinolytic factors at the individual animal level.

Free Research Field

環境健康学, 分子毒性学

Academic Significance and Societal Importance of the Research Achievements

世界各地でヒ素の地下水汚染による健康被害が発生しているものの、その毒性発現に関わる分子メカニズムは十分に解明されていない。ヒ素は血液凝固・線溶系の破綻を介して動脈硬化症や循環器障害を引き起こすことも示唆されているが、その毒性発現メカニズムの詳細も不明であった。本研究で得られた成果は、ヒ素をはじめとする有害環境汚染物質の血管毒性発現メカニズムに関する解明研究に新たな知見を提供すると共に、ヒ素曝露患者の予防と治療に貢献できるものと考えられる。