Lim Kyung-Min, Kim Sujin, Noh Ji-Yoon, Kim Keunyoung, Jang Won-Hee, Bae Ok-Nam, Chung Seung-Min, Chung Jin-Ho
Seoul National University, Korea.
Environ Health Perspect. 2010 Jul;118(7):928-35. doi: 10.1289/ehp.0901473. Epub 2010 Mar 12.
Associations between cardiovascular diseases and mercury have been frequently described, but underlying mechanisms are poorly understood.
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.
We used freshly isolated human erythrocytes and ex vivo and in vivo thrombosis models in rats to investigate mercury-induced procoagulant activity.
Prolonged exposure to low-dose mercuric ion (Hg(2+); 0.25-5 microM for 1-48 hr) induced erythrocyte shape changes from discocytes to echinocytes to spherocytes, accompanied by microvesicle (MV) generation. These MVs and remnant erythrocytes expressed phosphatidylserine (PS), an important mediator of procoagulant activation. Hg(2+) 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, Hg(2+) increased intracellular calcium and depleted ATP and protein thiol. A thiol supplement reversed Hg(2+)-induced MV generation and PS exposure and inhibited the increase in calcium ion (Ca(2+)) and depletion of ATP, indicating that free-thiol depletion was critical to Hg(2+)-mediated procoagulant activity. The procoagulant activity of Hg(2+)-treated erythrocytes was demonstrated by increased thrombin generation and endothelial cell adhesion. We further confirmed Hg(2+)-mediated procoagulant activation of erythrocytes in ex vivo and in vivo rat thrombosis models, where Hg(2+) treatment (0.5-2.5 mg/kg) increased PS exposure and thrombus formation significantly.
This study demonstrated that mercury could provoke procoagulant activity in erythrocytes through protein-thiol depletion-mediated PS exposure and MV generation, ultimately leading to enhanced thrombosis.
心血管疾病与汞之间的关联已被频繁描述，但潜在机制尚不清楚。
我们研究低水平汞对红细胞促凝激活作用，红细胞是血栓形成的重要因素，以探讨红细胞在汞相关心血管疾病中的作用。
我们使用新鲜分离的人红细胞以及大鼠体内和体外血栓形成模型来研究汞诱导的促凝活性。
长时间暴露于低剂量汞离子（Hg(2+)；0.25 - 5 microM，持续1 - 48小时）会使红细胞形状从双凹圆盘状变为棘状细胞再变为球形细胞，同时伴有微泡（MV）生成。这些微泡和残余红细胞表达磷脂酰丝氨酸（PS），这是促凝激活的重要介质。Hg(2+)抑制了将PS恢复到细胞膜内小叶的翻转酶，并激活了改变细胞膜脂质不对称性的 scramblase。与这些活性变化一致，Hg(2+)增加了细胞内钙并消耗了ATP和蛋白质巯基。巯基补充剂可逆转Hg(2+)诱导的MV生成和PS暴露，并抑制钙离子（Ca(2+)）的增加和ATP的消耗，表明游离巯基的消耗对于Hg(2+)介导的促凝活性至关重要。Hg(2+)处理的红细胞的促凝活性通过凝血酶生成增加和内皮细胞粘附得以证明。我们进一步在大鼠体内和体外血栓形成模型中证实了Hg(2+)介导的红细胞促凝激活，其中Hg(2+)处理（0.5 - 2.5 mg/kg）显著增加了PS暴露和血栓形成。
本研究表明汞可通过蛋白质巯基消耗介导的PS暴露和MV生成引发红细胞促凝活性，最终导致血栓形成增强。
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