Zinc is a transmembrane agonist that induces platelet activation in a tyrosine phosphorylation-dependent manner.

Ben R Watson,Nicholas Pugh,Jean-Daniel M Malcor,Stewart O Sage,Richard W Farndale,Joanna-Marie Howes,Nathan A White,Kirk A Taylor,Dominique Bihan

doi:10.1039/c5mt00064e

Abstract

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.

Highlights

Platelets are the principal cellular determinants of haemostasis and pathological thrombus formation leading to myocardial infarction and stroke
Previous studies have shown that 0.5 mM ZnCl2 induces aggregation in both platelet rich plasma (PRP) and washed platelets, and that increasing the concentration further results in a reduced response.[15,16]
Platelet aggregation induced by CRP-XL, U46619 or ZnSO4 was fully abrogated in TPEN-treated platelets, whilst aggregation induced by thrombin or A23187 was inhibited at low agonist concentrations (Fig. 7A–E)

Summary

Introduction

Platelets are the principal cellular determinants of haemostasis and pathological thrombus formation leading to myocardial infarction and stroke. Following adhesion to sites of vascular damage, platelets undergo primary activation leading to shape change, upregulation of integrin aIIbb[3] activity and secretion of alpha and dense granules.[1] Granule release introduces bioactive molecules into the immediate environment of a growing thrombus. Such molecules include adhesion proteins, coagulation factors and soluble platelet agonists, such as ADP, ATP, thromboxane-A2 and zinc.[2,3,4]. Our data are consistent with a role for zinc in platelet activation during haemostasis and pathogenic thrombus formation

Results

Conclusions

Ethical approval