Low-Level Mercury Can Enhance Procoagulant Activity of Erythrocytes: A New Contributing Factor for Mercury-Related Thrombotic Disease
Low-Level Mercury Can Enhance Procoagulant Activity of Erythrocytes: A New Contributing Factor for Mercury-Related Thrombotic Disease
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DOI：
10.1289/ehp.0901473
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发表时间：
2010-07-01
影响因子：
10.4
通讯作者：
Chung, Jin-Ho
中科院分区：
文献类型：
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作者：
Lim, Kyung-Min;Kim, Sujin;Chung, Jin-Ho
背景：人们经常描述心血管疾病和汞之间的关联，但对其潜在机制了解甚少。目的：研究低水平汞对红细胞促凝激活的影响，探讨红细胞在汞相关心血管疾病中的作用。方法：采用新鲜分离的人红细胞和大鼠离体和体内血栓形成模型，研究汞诱导的促凝剂活性。结果：长时间暴露于低剂量汞离子（Hg2+; 0.25-5 μ M，持续1-48小时）可诱导红细胞形态发生变化，从盘状细胞到棘球细胞再到球形细胞，并伴有微囊泡（MV）的产生。这些mv和残余红细胞表达磷脂酰丝氨酸（PS），一种重要的促凝剂激活介质。Hg2+抑制翻转酶（一种将PS恢复到细胞膜内小叶的酶），并激活超燃酶（一种改变细胞膜脂质不对称的酶）。与这些活性变化一致，Hg2+增加了细胞内钙，减少了ATP和蛋白硫醇。补充硫醇可逆转Hg2+诱导的MV生成和PS暴露，并抑制钙离子（Ca2+）的增加和ATP的消耗，表明游离硫醇的消耗对Hg2+介导的促凝活性至关重要。Hg2+处理红细胞的促凝活性通过凝血酶生成和内皮细胞粘附的增加得到证实。在离体和体内大鼠血栓模型中，我们进一步证实了Hg2+介导的促凝剂对红细胞的激活作用，其中Hg2+处理（0.5-2.5 mg/kg）显著增加了PS暴露和血栓形成。结论：本研究表明，汞可通过蛋白巯基消耗介导的PS暴露和MV生成，刺激红细胞促凝活性，最终导致血栓形成增强。
BACKGROUND: Associations between cardiovascular diseases and mercury have been frequently described, but underlying mechanisms are poorly understood.OBJECTIVES: We investigate the procoagulant activation of erythrocytes, an important contributor to thrombosis, by low-level mercury to explore the roles of erythrocytes in mercury-related cardiovascular diseases.METHODS: We used freshly isolated human erythrocytes and ex vivo and in vivo thrombosis models in rats to investigate mercury-induced procoagulant activity.RESULTS: Prolonged exposure to low-dose mercuric ion (Hg2+; 0.25-5 mu M for 1-48 hr) induced erythrocyte shape changes from discocytes to echinocytes to spherocytes, accompanied by micro-vesicle (MV) generation. These MVs and remnant erythrocytes expressed phosphatidylserine (PS), an important mediator of procoagulant activation. Hg2+ inhibited flippase, an enzyme that recovers PS into the inner leaflet of the cell membrane, and activated scramblase, an enzyme that alters lipid asymmetry in the cell membrane. Consistent with these activity changes, Hg2+ increased intracellular calcium and depleted ATP and protein thiol. A thiol supplement reversed Hg2+-induced MV generation and PS exposure and inhibited the increase in calcium ion (Ca2+) and depletion of ATP, indicating that free-thiol depletion was critical to Hg2+-mediated procoagulant activity. The procoagulant activity of Hg2+-treated erythrocytes was demonstrated by increased thrombin generation and endothelial cell adhesion. We further confirmed Hg2+-mediated procoagulant activation of erythrocytes in ex vivo and in vivo rat thrombosis models, where Hg2+ treatment (0.5-2.5 mg/kg) increased PS exposure and thrombus formation significantly.CONCLUSION: This study demonstrated that mercury could provoke procoagulant activity in erythro-cytes through protein-thiol depletion-mediated PS exposure and MV generation, ultimately leading to enhanced thrombosis.