TY - JOUR
T1 - Platelet zinc status regulates prostaglandin-induced signaling, altering thrombus formation
AU - Coupland, Charlie A.
AU - Naylor-Adamson, Leigh
AU - Booth, Zoe
AU - Price, Thomas W.
AU - Gil, Helio M.
AU - Firth, George
AU - Avery, Michelle
AU - Ahmed, Yusra
AU - Stasiuk, Graeme J.
AU - Calaminus, Simon D.J.
N1 - Funding Information:
Funding information British Heart Foundation; PhD studentships Grant Number: FS/19/38/34441 (to C.A.C.) and FS/16/62/32220 (to M.A.) University of Hull (PhD fellowships [to Z.B. and Y.A.]) MRC; Grant Number: MR/T002573/1 (to G.J.S., T.W.P., and L.N.-A.).
Publisher Copyright:
© 2023 The Authors
PY - 2023/9
Y1 - 2023/9
N2 - 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.
AB - 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.
KW - adenylyl cyclase
KW - bleeding
KW - prostacyclin
KW - zinc (Zn)
UR - http://www.scopus.com/inward/record.url?scp=85163403334&partnerID=8YFLogxK
U2 - 10.1016/j.jtha.2023.05.008
DO - 10.1016/j.jtha.2023.05.008
M3 - Article
C2 - 37210073
AN - SCOPUS:85163403334
SN - 1538-7933
VL - 21
SP - 2545
EP - 2558
JO - JOURNAL OF THROMBOSIS AND HAEMOSTASIS
JF - JOURNAL OF THROMBOSIS AND HAEMOSTASIS
IS - 9
ER -