IN-VIVO FORMATION OF 8-EPI-PROSTAGLANDIN F2-ALPHA IS INCREASED IN HYPERCHOLESTEROLEMIA

F-2-isoprostanes are bioactive prostaglandin (PG)-like compounds that are produced from arachidonic acid through a nonenzymatic process of l ipid peroxidation catalyzed by oxygen free-radicals. 8-Epi-PGF(2 alpha ) may amplify the platelet response to agonists, circulates in plasma, and is excreted in urine. We examined the hypothesis that the formati on of 8-epi-PGF(2 alpha) is altered in patients with hypercholesterole mia and contributes to platelet activation in this setting. Urine samp les were obtained from 40 hypercholesterolemic patients and 40 age- an d sex-matched control subjects for measurement of immunoreactive 8-epi -PGF(2 alpha). Urinary excretion of 11-dehydro-thromboxane (TX) B-2, a major metabolite of TXA(2), was measured as an in vivo index of plate let activation. Low-dose aspirin, indobufen, and vitamin E were used t o investigate the mechanism of formation and effects of 8-epi-PGF(2 al pha) on platelet activation. Urinary 8-epi-PGF(2 alpha) was significan tly (P = .0001) higher in hypercholesterolemic patients than in contro l subjects: 473 +/- 305 versus 205 +/- 95 pg/mg creatinine. Its rate o f excretion was inversely related to the vitamin E content of LDL and showed a positive correlation with urinary 11-dehydro-TXB2. Urinary 8- epi-PGF(2 alpha) was unchanged after 2-week dosing with aspirin and in dobufen despite complete suppression of TX metabolite excretion. Vitam in E supplementation was associated with dose-dependent reductions in both urinary 8-epi-PGF(2 alpha) and 11-dehydro-TXB2 by 34% to 36% and 47% to 58% at 100 and 600 mg daily, respectively. We conclude that the in vivo formation of the F-2-isoprostane 8-epi-PGF(2 alpha) is enhanc ed in the vast majority of patients with hypercholesterolemia. This pr ovides an aspirin-insensitive mechanism possibly linking lipid peroxid ation to amplification of platelet activation in the setting of hyperc holesterolemia. Dose-dependent suppression of enhanced 8-epi-PGF(2 alp ha) formation by vitamin E supplementation may contribute to the benef icial effects of antioxidant treatment.