Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:3230-3235
© 1997 American Heart Association, Inc.
Articles |
In Vivo Formation of 8-Epi-Prostaglandin F2
Is Increased in Hypercholesterolemia
From the Departments of Medicine (G.D. A.M., F. Costantini, F. Cipollone), Pharmacology (C.P.), and Biochemistry (T.B.), University of Chieti "G. D'Annunzio" School of Medicine, Chieti; the Department of Pharmacology, Catholic University School of Medicine, Rome (G.M., G.C.); and the Division of Internal Medicine, Civil Hospital of Venice (P.A., G.B.B.), Italy.
Correspondence to Carlo Patrono, MD, Cattedra di Farmacologia I, Universita degli Studi "G. D'Annunzio," Via del Vestini 31, 66013 Chieti, Italy. E-mail cpatrono{at}unich.it
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 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 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. 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 on platelet activation.
Urinary 8-epi-PGF2 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 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 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 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 formation
by vitamin E supplementation may contribute to the beneficial effects
of antioxidant treatment.
Key Words: aspirin • F2-isoprostanes • thromboxane • hypercholesterolemia • vitamin E
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