title: In vivo formation of 8-Epi-prostaglandin F2 alpha is increased in hypercholesterolemia.
abstract: F2-isoprostanes are bioactive prostaglandin (PG)-like compounds that are produced from arachidonic acid through a nonenzymatic process of lipid peroxidation catalyzed by oxygen free-radicals. 8-Epi-PGF2 alpha may amplify the platelet response to agonists, circulates in plasma, and is excreted in urine. We examined the hypothesis that the formation of 8-epi-PGF2 alpha is altered in patients with hypercholesterolemia and contributes to platelet activation in this setting. Urine samples were obtained from 40 hypercholesterolemic patients and 40 age- and sex-matched control subjects for measurement of immunoreactive 8-epi-PGF2 alpha. Urinary excretion of 11-dehydro-thromboxane (TX) B2, a major metabolite of TXA2, was measured as an in vivo index of platelet activation. Low-dose aspirin, indobufen, and vitamin E were used to investigate the mechanism of formation and effects of 8-epi-PGF2 alpha on platelet activation. Urinary 8-epi-PGF2 alpha was significantly (P = .0001) higher in hypercholesterolemic patients than in control subjects: 473 +/- 305 versus 205 +/- 95 pg/mg creatinine. Its rate of excretion was inversely related to the vitamin E content of LDL and showed a positive correlation with urinary 11-dehydro-TXB2. Urinary 8-epi-PGF2 alpha was unchanged after 2-week dosing with aspirin and indobufen despite complete suppression of TX metabolite excretion. Vitamin E supplementation was associated with dose-dependent reductions in both urinary 8-epi-PGF2 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 F2-isoprostane 8-epi-PGF2 alpha is enhanced in the vast majority of patients with hypercholesterolemia. This provides an aspirin-insensitive mechanism possibly linking lipid peroxidation to amplification of platelet activation in the setting of hypercholesterolemia. Dose-dependent suppression of enhanced 8-epi-PGF2 alpha formation by vitamin E supplementation may contribute to the beneficial effects of antioxidant treatment.
authors.affiliation: Department of Medicine, University of Chieti G. D'Annunzio, School of Medicine, Chieti, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Davi
authors.forename: P
authors.initials: P
authors.lastname: Alessandrini
authors.forename: A
authors.initials: A
authors.lastname: Mezzetti
authors.forename: G
authors.initials: G
authors.lastname: Minotti
authors.forename: T
authors.initials: T
authors.lastname: Bucciarelli
authors.forename: F
authors.initials: F
authors.lastname: Costantini
authors.forename: F
authors.initials: F
authors.lastname: Cipollone
authors.forename: G B
authors.initials: GB
authors.lastname: Bon
authors.forename: G
authors.initials: G
authors.lastname: Ciabattoni
authors.forename: C
authors.initials: C
authors.lastname: Patrono
mesh_terms: D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D001241:Aspirin / Q000494:pharmacology / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000209:etiology / Q000517:prevention & control; D003430:Cross-Sectional Studies; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000235:genetics / Q000652:urine; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000378:metabolism*; D054833:Isoindoles; D015227:Lipid Peroxidation / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000097:blood / Q000737:chemistry; D008297:Male; D008875:Middle Aged; D010654:Phenylbutyrates / Q000494:pharmacology / Q000627:therapeutic use; D015539:Platelet Activation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D017382:Reactive Oxygen Species; D013929:Thromboxane B2 / Q000031:analogs & derivatives / Q000652:urine; D014810:Vitamin E / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000975:Antioxidants; D016861:Cyclooxygenase Inhibitors; D054833:Isoindoles; D008077:Lipoproteins, LDL; D010654:Phenylbutyrates; D010975:Platelet Aggregation Inhibitors; D017382:Reactive Oxygen Species; D014810:Vitamin E; C075750:8-epi-prostaglandin F2alpha; D013929:Thromboxane B2; C049235:11-dehydro-thromboxane B2; C020371:indobufen; D015237:Dinoprost; D001241:Aspirin