The F₂-Isoprostane 8-Epiprostaglandin F₂ Increases Platelet Adhesion and Reduces the Antiadhesive and Antiaggregatory Effects of NO

From the Institutes of Clinica Medica (P.M., M.D., A.L.), Chimica e Microscopia Clinica (G.A., S.G., R.T., V.Z., C.L.), and Immunologia e Malattie Infettive (R.O.), University of Verona, Verona, Italy.

Correspondence to Dr P. Minuz, Clinica Medica, Policlinico di Borgo Roma, Via delle Menegone, 37134 Verona, Italy.

Abstract—F₂-isoprostanes are prostaglandin (PG) isomers produced in vivo through free radical–catalyzed peroxidation of arachidonic acid, which may affect platelet function. The current study investigated the effects of 8-epiprostaglandin F₂ (8-epi-PGF₂) on critical events of platelet activation. A dose-dependent increase in platelet adhesion to fibrinogen- and plasma-coated microwells by 8-epi-PGF₂ (1 to 1000 nmol/L) was observed when resting platelets (plasma from 1.3±0.2% to 5.5±0.2%, EC₅₀ of 48 nmol/L; fibrinogen from 3.3±0.3% to 6.4±0.2%, EC₅₀ of 35 nmol/L; mean±SEM, n=8, P<0.001) and thrombin-stimulated human platelets were used. The expression of the adhesion molecule glycoprotein IIb/IIIa was increased by 10 to 1000 nmol/L 8-epi-PGF₂ in resting platelets (from 64.8±2.1% to 83.9±1.3%; n=5, P<0.01) and in stimulated platelets. The secretion of the glycoprotein GMP-140 increased only in the presence of both thrombin and 10 to 1000 nmol/L 8-epi-PGF₂ (from 48.5±3.1% to 63.1±2.0%, P<0.05). The antiaggregatory effects of both the NO donor NOR-3 (basal, 21.4±4.6%; with 8-epi-PGF₂, 30.8±6.9%; n=14, P<0.05) and endothelial cells that release NO (basal, 18.5±4.6%; with 8-epi-PGF₂, 30.7±5.3%; n=15, P<0.001) were also reduced. All of these effects were prevented by the thromboxane receptor antagonist GR32191 but not affected by acetylsalicylic acid. An increase in free intracellular calcium concentration, measured with the use of fura 2, was observed with 8-epi-PGF₂. In conclusion, F₂-isoprostanes may participate in oxidative injury by inducing platelet activation and by reducing the antiplatelet activity of NO: increased platelet adhesiveness and expression of the fibrinogen receptor are induced by nanomolar amounts of 8-epi-PG-F₂. Platelet secretion and aggregation can also be induced in the presence of platelet agonists.

Key Words: F₂-isoprostanes • platelet adhesion • nitric oxide

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