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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)2545-2558
Number of pages14
JournalJOURNAL OF THROMBOSIS AND HAEMOSTASIS
Volume21
Issue number9
Early online date18 May 2023
DOIs
Publication statusPublished - Sept 2023

Keywords

  • adenylyl cyclase
  • bleeding
  • prostacyclin
  • zinc (Zn)

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