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

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.

To investigate if Zn²⁺ can modulate platelet PGI₂ signaling.

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.

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 pVASP^ser157, 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.

Zn²⁺ chelation potentiates platelet PGI₂ signaling, elevating PGI₂'s ability to prevent effective platelet activation, aggregation, and thrombus formation.