Watson Ben R, White Nathan A, Taylor Kirk A, Howes Joanna-Marie, Malcor Jean-Daniel M, Bihan Dominique, Sage Stewart O, Farndale Richard W, Pugh Nicholas
Department of Biochemistry, University of Cambridge, Downing Site, Cambridge, UK.
Department of Biomedical and Forensic Sciences, Anglia Ruskin University, East Road, Cambridge, UK.
Metallomics. 2016 Jan;8(1):91-100. doi: 10.1039/c5mt00064e.
Following platelet adhesion and primary activation at sites of vascular injury, secondary platelet activation is induced by soluble platelet agonists, such as ADP, ATP, thrombin and thromboxane. Zinc ions are also released from platelets and damaged cells and have been shown to act as a platelet agonist. However, the mechanism of zinc-induced platelet activation is not well understood. Here we show that exogenous zinc gains access to the platelet cytosol and induces full platelet aggregation that is dependent on platelet protein tyrosine phosphorylation, PKC and integrin αIIbβ3 activity and is mediated by granule release and secondary signalling. ZnSO4 increased the binding affinity of GpVI, but not integrin α2β1. Low concentrations of ZnSO4 potentiated platelet aggregation by collagen-related peptide (CRP-XL), thrombin and adrenaline. Chelation of intracellular zinc reduced platelet aggregation induced by a number of different agonists, inhibited zinc-induced tyrosine phosphorylation and inhibited platelet activation in whole blood under physiologically relevant flow conditions. Our data are consistent with a transmembrane signalling role for zinc in platelet activation during thrombus formation.
在血管损伤部位血小板黏附和初步激活后，可溶性血小板激动剂如ADP、ATP、凝血酶和血栓烷会诱导血小板的二次激活。锌离子也从血小板和受损细胞中释放出来，并已被证明可作为血小板激动剂。然而，锌诱导血小板激活的机制尚不清楚。在此我们表明，外源性锌进入血小板胞质溶胶并诱导完全的血小板聚集，这依赖于血小板蛋白酪氨酸磷酸化、蛋白激酶C（PKC）和整合素αIIbβ3活性，并由颗粒释放和二次信号传导介导。硫酸锌增加了糖蛋白VI（GpVI）的结合亲和力，但未增加整合素α2β1的结合亲和力。低浓度的硫酸锌增强了胶原相关肽（CRP-XL）、凝血酶和肾上腺素诱导的血小板聚集。细胞内锌的螯合减少了多种不同激动剂诱导的血小板聚集，抑制了锌诱导的酪氨酸磷酸化，并在生理相关流动条件下抑制了全血中的血小板激活。我们的数据与锌在血栓形成过程中血小板激活中的跨膜信号传导作用一致。
