Abstract 5301: Fractalkine Desensitizes Platelets to Platelet Inhibition by the Endogenous Platelet Inhibitor Prostacyclin
Background: Fractalkine plays a pivotal role in atherogenesis. Platelet activation is a central factor in atherosclerosis progression. We previously reported that fractalkine induces platelet degranulation and P-selectin expression facilitating platelet-leukocyte adhesion. Fractalkine attenuates the bioavailability of the important endogenous platelet inhibitor nitric oxide.
Methods: The influence of preincubation of platelets with fractalkine (1 μg/ml) on platelet inhibition by the platelet inhibitor prostaglandin E1 (PGE1) was assessed by two assays: first, the ability to prevent PGE1-induced attenuation of ADP-induced platelet aggregation, and second, the capability to decrease PGE1-induced vasodilator-stimulated phosphoprotein (VASP)-phosphorylation determined by flow-cytometry. Samples were preincubated with fractalkine and stimulated with different concentrations of PGE1.
Results: PGE1 significantly inhibited ADP-induced platelet aggregation. In samples pre-treated with fractalkine, prevention of ADP-induced platelet aggregation by PGE1was abrogated. While secondary platelet aggregation was prevented by PGE1 (1 μM), preincubation with fractalkine for 10 minutes reestablished secondary platelet aggregation. These results indicate that fractalkine desensitized platelets to PGE1. PGE1-induced VASP-phosphorylation was significantly attenuated by preincubation with fractalkine in a time- and concentration-dependent pattern, whereby a maximum effect was achieved after preincubation of platelets with fractalkine for 10 minutes, which reduced PGE1 (1 μM)-induced VASP-phosphorylation by ~25% (p<0.01 vs. PGE1 without fractalkine).
Conclusion: Fractalkine desensitizes platelets to PGE1 suggesting that platelet inhibition by the endogenous platelet inhibitor prostacyclin is affected by fractalkine. These results indicate a new pathomechanism by which this atherogenic chemokine facilitates relevant steps leading to platelet activation and leukocyte recruitment, namely rendering platelets less responsive to endogenous platelet inhibition.