Arsenic, an environmental contaminant in drinking water worldwide is well-established to increase cardiovascular diseases (CVDs) in humans. Of these, thrombotic events represent a major adverse effect associated with arsenic exposure, for which an abundance of epidemiological evidence exists. Platelet aggregation constitutes a pivotal step in thrombosis but arsenic alone doesn't induce aggregation and the mechanism underlying arsenic-induced thrombosis still remains unclear. Here we demonstrated that arsenic induces morphological changes of platelets, i.e., contraction and pseudopod projection, the primal events of platelet activation, which can increase platelet reactivity. Arsenite induced prominent platelet shape changes in a dose-dependent manner in freshly isolated human platelets. Of note, arsenite suppressed focal adhesion kinase (FAK) activity, which in turn activated RhoA, leading to altered actin assembly through LIMK activation, and subsequent cofilin inactivation. Arsenic-induced platelet shape change appeared to increase the sensitivity to thrombin and ADP-induced aggregation. Supporting this, latrunculin A, an inhibitor of actin-dynamics abolished it. Taken together, we demonstrated that arsenic induces cytoskeletal changes and shape changes of platelets through FAK-mediated alteration of actin dynamics, which renders platelets reactive to activating stimuli, ultimately contributing to increased thrombosis.

中文翻译：

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砷通过改变粘着斑激酶介导的肌动蛋白动力学来诱导血小板形状改变，从而有助于提高血小板反应性。

砷是全世界饮用水中的一种环境污染物，已被公认可以增加人类的心血管疾病（CVD）。其中，血栓形成事件是与砷暴露相关的主要不良反应，为此存在大量的流行病学证据。血小板凝集是血栓形成的关键步骤，但仅砷不会诱导凝集，而砷诱导的血栓形成的机制仍不清楚。在这里，我们证明了砷诱导了血小板的形态变化，即收缩和假足投射，这是血小板活化的主要事件，可以增加血小板的反应性。在新鲜分离的人血小板中，亚砷酸盐以显着的剂量依赖性诱导了明显的血小板形状变化。值得注意的是 亚砷酸盐抑制了粘着斑激酶（FAK）的活性，从而激活了RhoA，从而通过LIMK激活和随后的cofilin失活导致肌动蛋白装配改变。砷诱导的血小板形状改变似乎增加了对凝血酶和ADP诱导的聚集的敏感性。支持这一点的肌动蛋白动力学抑制剂拉特朗库林A废除了它。综上所述，我们证明了砷通过FAK介导的肌动蛋白动力学变化诱导细胞骨架变化和血小板形状变化，从而使血小板对激活刺激具有反应性，最终导致血栓形成增加。砷诱导的血小板形状改变似乎增加了对凝血酶和ADP诱导的聚集的敏感性。支持这一点的肌动蛋白动力学抑制剂拉特朗库林A废除了它。综上所述，我们证明了砷通过FAK介导的肌动蛋白动力学变化诱导细胞骨架变化和血小板形状变化，从而使血小板对激活刺激具有反应性，最终导致血栓形成增加。砷诱导的血小板形状改变似乎增加了对凝血酶和ADP诱导的聚集的敏感性。支持这一点的肌动蛋白动力学抑制剂拉特朗库林A废除了它。综上所述，我们证明了砷通过FAK介导的肌动蛋白动力学变化诱导细胞骨架变化和血小板形状变化，从而使血小板对激活刺激具有反应性，最终导致血栓形成增加。