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Platelet zinc status regulates prostaglandin-induced signaling, altering thrombus formation

Coupland, Charlie A.; Naylor-Adamson, Leigh; Booth, Zoe; Price, Thomas W.; Gil, Helio M.; Firth, George; Avery, Michelle; Ahmed, Yusra; Stasiuk, Graeme J.; Calaminus, Simon D.J.

Authors

Charlie A. Coupland

Leigh Naylor-Adamson

Zoe Booth

Thomas W. Price

Helio M. Gil

George Firth

Michelle Avery

Yusra Ahmed

Graeme J. Stasiuk



Abstract

Background: Approximately 17.3% of the global population exhibits an element of zinc (Zn2+) deficiency. One symptom of Zn2+ deficiency is increased bleeding through impaired hemostasis. Platelets are crucial to hemostasis and are inhibited by endothelial-derived prostacyclin (prostaglandin I2 [PGI2]), which signals via adenylyl cyclase (AC) and cyclic adenosine monophosphate signaling. In other cell types, Zn2+ modulates cyclic adenosine monophosphate concentrations by changing AC and/or phosphodiesterase activity. Objectives: To investigate if Zn2+ can modulate platelet PGI2 signaling. Methods: Platelet aggregation, spreading, and western blotting assays with Zn2+ chelators and cyclic nucleotide elevating agents were performed in washed platelets and platelet-rich plasma conditions. In vitro thrombus formation with various Zn2+ chelators and PGI2 was assessed in whole blood. Results: Incubation of whole blood or washed platelets with Zn2+ chelators caused either embolization of preformed thrombi or reversal of platelet spreading, respectively. To understand this effect, we analyzed resting platelets and identified that incubation with Zn2+ chelators elevated pVASPser157, a marker of PGI2 signaling. In agreement that Zn2+ affects PGI2 signaling, addition of the AC inhibitor SQ22536 blocked Zn2+ chelation–induced platelet spreading reversal, while addition of Zn2+ blocked PGI2-mediated platelet reversal. Moreover, Zn2+ specifically blocked forskolin-mediated AC reversal of platelet spreading. Finally, PGI2 inhibition of platelet aggregation and in vitro thrombus formation was potentiated in the presence of low doses of Zn2+ chelators, increasing its effectiveness in inducing platelet inhibition. Conclusion: Zn2+ chelation potentiates platelet PGI2 signaling, elevating PGI2’s ability to prevent effective platelet activation, aggregation, and thrombus formation.

Citation

Coupland, C. A., Naylor-Adamson, L., Booth, Z., Price, T. W., Gil, H. M., Firth, G., …Calaminus, S. D. (2023). Platelet zinc status regulates prostaglandin-induced signaling, altering thrombus formation. Journal of thrombosis and haemostasis : JTH, 21(9), 2545-2558. https://doi.org/10.1016/j.jtha.2023.05.008

Journal Article Type Article
Acceptance Date May 7, 2023
Online Publication Date May 18, 2023
Publication Date Sep 1, 2023
Deposit Date May 30, 2023
Publicly Available Date Aug 18, 2023
Journal Journal of Thrombosis and Haemostasis
Print ISSN 1538-7933
Electronic ISSN 1538-7836
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 21
Issue 9
Pages 2545-2558
DOI https://doi.org/10.1016/j.jtha.2023.05.008
Keywords Adenylyl cyclase; Bleeding; Prostacyclin; Zinc (Zn2+)
Public URL https://hull-repository.worktribe.com/output/4301170
Additional Information This article is maintained by: Elsevier; Article Title: Platelet Zinc status regulates prostaglandin-induced signaling altering thrombus formation; Journal Title: Journal of Thrombosis and Haemostasis; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.jtha.2023.05.008; Content Type: article; Copyright: © 2023 The Authors. Published by Elsevier Inc. on behalf of International Society on Thrombosis and Haemostasis.

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