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

by Selleckchem | Oct 18 2023

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.

Comments:

Summary: The study aimed to investigate whether zinc (Zn2+) can modulate platelet signaling through prostacyclin (PGI2), an endothelial-derived molecule that inhibits platelet function. The researchers performed various assays using platelets and whole blood to assess the effects of Zn2+ chelators and cyclic nucleotide elevating agents on platelet aggregation, spreading, and thrombus formation.

The results showed that incubation of whole blood or washed platelets with Zn2+ chelators led to the embolization of preformed blood clots or the reversal of platelet spreading, respectively. The researchers observed an increase in the phosphorylation of vasodilator-stimulated phosphoprotein (pVASPser157), a marker of PGI2 signaling, in resting platelets treated with Zn2+ chelators. This finding suggested that Zn2+ chelation enhanced PGI2 signaling.

Further experiments revealed that the addition of an adenylyl cyclase (AC) inhibitor blocked the Zn2+ chelation-induced reversal of platelet spreading, while the addition of Zn2+ blocked the platelet-reversing effects of PGI2. Additionally, Zn2+ specifically inhibited the AC-mediated reversal of platelet spreading induced by forskolin. Furthermore, the researchers found that low doses of Zn2+ chelators potentiated the inhibitory effects of PGI2 on platelet aggregation and in vitro thrombus formation, increasing its effectiveness in preventing platelet activation.

In conclusion, the study demonstrated that Zn2+ chelation enhances platelet PGI2 signaling, leading to increased inhibition of platelet activation, aggregation, and thrombus formation. These findings suggest that Zn2+ plays a regulatory role in platelet function and provide insights into the potential implications of zinc deficiency in hemostasis.