9/26/2023 0 Comments Zinc reactivity![]() ![]() This is exemplified by impaired platelet reactivity and haemostatic defects in patients and animal models with dietary Zn 2+ deficiency ( 12, 13). Zn 2+ is present in the plasma at a concentration of 20-30 µM (with 0.5 µM in a free, non-protein bound form) and contributes to thrombosis and haemostasis by modulating platelet activation and coagulation ( 7– 11). Zn 2+ binds to nearly 10% of the human proteome to act as a cofactor for maintaining normal cellular signalling ( 2, 5, 6). Cellular Zn 2+ exists tightly or loosely protein-bound but also in a free or non-proteinous ligand-bound status referred to as mobile or labile zinc ( 3). In the human body, plasma contains 0.1% of total Zn 2+, while the majority of Zn 2+ content is present intracellularly ( 3, 4). Zinc (Zn 2+) is an essential micronutrient that represents the second most abundant transition element in the body next to iron ( 1, 2). The current study thereby identifies ZIP1 and ZIP3 as important regulators for the maintenance of platelet Zn 2+ homeostasis and function. Molecularly, augmented GPCR responses were accompanied by enhanced Ca 2+ and PKC, CamKII and ERK1/2 signalling. This resulted in enhanced platelet aggregation towards thrombin, bigger thrombus volume under flow ex vivo and faster in vivo thrombus formation in ZIP1/3 DKO mice. 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. While ICP-MS measurements indicated unaltered overall Zn 2+ concentrations in platelets of ZIP1/3 DKO mice, we observed a significantly increased content of FluoZin3-stainable free Zn 2+, which, however, appears to be released less efficiently upon thrombin-stimulated platelet activation. ![]() Using mice globally lacking ZIP1 and ZIP3 (ZIP1/3 DKO), our aim was to explore the potential role of these Zn 2+ transporters in maintaining platelet Zn 2+ homeostasis and in the regulation of platelet function. Zn 2+ transporters, ZIPs and ZnTs, are widely expressed in eukaryotic cells. However, our understanding of the transport mechanisms that regulate Zn 2+ homeostasis in platelets is limited. Zinc (Zn 2+) is considered as important mediator of immune cell function, thrombosis and haemostasis. 3Department for Functional Materials in Medicine and Dentistry, University Hospital Würzburg, Würzburg, Germany.2Institute of Experimental Biomedicine I, University Hospital Würzburg and Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany.1Medical Clinic II, Division of Hepatology, University Hospital Würzburg, Würzburg, Germany.Bösl 2† Harald Schulze 2† Bernhard Nieswandt 2† Timo Vögtle 2*† Heike M. Amro Elgheznawy 1 Patricia Öftering 2† Maximilian Englert 2† Kristina Mott 2† Friederike Kaiser 3† Charly Kusch 2† Uwe Gbureck 3† Michael R. ![]()
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