Medical Clinic II, Division of Hepatology, University Hospital Würzburg, Würzburg, Germany.
Institute of Experimental Biomedicine I, University Hospital Würzburg and Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany.
Front Immunol. 2023 Jun 8;14:1197894. doi: 10.3389/fimmu.2023.1197894. eCollection 2023.
Zinc (Zn) is considered as important mediator of immune cell function, thrombosis and haemostasis. However, our understanding of the transport mechanisms that regulate Zn homeostasis in platelets is limited. Zn transporters, ZIPs and ZnTs, are widely expressed in eukaryotic cells. Using mice globally lacking ZIP1 and ZIP3 (ZIP1/3 DKO), our aim was to explore the potential role of these Zn transporters in maintaining platelet Zn homeostasis and in the regulation of platelet function. While ICP-MS measurements indicated unaltered overall Zn concentrations in platelets of ZIP1/3 DKO mice, we observed a significantly increased content of FluoZin3-stainable free Zn, which, however, appears to be released less efficiently upon thrombin-stimulated platelet activation. On the functional level, ZIP1/3 DKO platelets exhibited a hyperactive response towards threshold concentrations of G protein-coupled receptor (GPCR) agonists, while immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptor agonist signalling was unaffected. This resulted in enhanced platelet aggregation towards thrombin, bigger thrombus volume under flow and faster thrombus formation in ZIP1/3 DKO mice. Molecularly, augmented GPCR responses were accompanied by enhanced Ca and PKC, CamKII and ERK1/2 signalling. The current study thereby identifies ZIP1 and ZIP3 as important regulators for the maintenance of platelet Zn homeostasis and function.
锌 (Zn) 被认为是免疫细胞功能、血栓形成和止血的重要介质。然而，我们对调节血小板中 Zn 动态平衡的转运机制的理解有限。Zn 转运蛋白，包括 ZIPs 和 ZnTs，广泛表达于真核细胞中。本研究使用在全球范围内缺乏 ZIP1 和 ZIP3 的小鼠（ZIP1/3 DKO），旨在探索这些 Zn 转运蛋白在维持血小板 Zn 动态平衡和调节血小板功能中的潜在作用。尽管 ICP-MS 测量表明 ZIP1/3 DKO 小鼠血小板中的总 Zn 浓度没有改变，但我们观察到 FluoZin3 可染色的游离 Zn 含量显著增加，然而，在凝血酶刺激的血小板激活时，其释放效率似乎较低。在功能水平上，ZIP1/3 DKO 血小板对 G 蛋白偶联受体 (GPCR) 激动剂的阈浓度表现出过度活跃的反应，而免疫受体酪氨酸基激活基序 (ITAM) 偶联受体激动剂信号不受影响。这导致 ZIP1/3 DKO 小鼠对凝血酶的血小板聚集增强，在流动条件下血栓体积更大，血栓形成速度更快。从分子水平上看，增强的 GPCR 反应伴随着 Ca 和 PKC、CamKII 和 ERK1/2 信号的增强。本研究因此确定 ZIP1 和 ZIP3 是维持血小板 Zn 动态平衡和功能的重要调节因子。
