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.

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., Avery, M., Ahmed, Y., Stasiuk, G. J., & 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.