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J Biol Chem, Vol. 273, Issue 47, 30879-30887, November 20, 1998
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From the A number of endothelium-derived
relaxing factors have been identified including nitric oxide,
prostacyclin, and the epoxyeicosatrienoic acids. Previous work showed
that in rabbit aortic endothelial cells, arachidonic acid was
metabolized by a lipoxygenase to vasodilatory eicosanoids. The identity
was determined by the present study. Aortic homogenates were incubated
in the presence of [U-14C]arachidonic acid,
[U-14C]arachidonic acid plus 15-lipoxygenase (soybean
lipoxidase), or [U-14C]15-hydroxyeicosatetraenoic acid
(15-HPETE) and analyzed by reverse phase high pressure liquid
chromatography (RP-HPLC). Under both experimental conditions, there was
a radioactive metabolite that migrated at 17.5-18.5 min on RP-HPLC.
When the metabolite was isolated from aortic homogenates, it relaxed
precontracted aortas in a concentration-dependent manner.
Gas chromatography/mass spectrometry (GC/MS) of the derivatized
metabolite indicated the presence of two products;
11,12,15-trihydroxyeicosatrienoic acid (THETA) and 11,14,15-THETA. A
variety of chemical modifications of the metabolite supported these
structures and confirmed the presence of a carboxyl group, double
bonds, and hydroxyl groups. With the combination of 15-lipoxygenase,
arachidonic acid, and aortic homogenate, an additional major
radioactive peak was observed. This fraction was analyzed by GC/MS. The
mass spectrum was consistent with this peak, containing both the
11-hydroxy-14,15-epoxyeicosatrienoic acid (11-H-14,15-EETA) and
15-H-11,12-EETA. The hydroxyepoxyeicosatrienoic acid (HEETA) fraction
also relaxed precontracted rabbit aorta. Microsomes derived from rabbit
aortas also synthesized 11,12,15- and 11,14,15-THETAs from 15-HPETE,
and pretreatment with the cyctochrome P450 inhibitor, miconazole,
blocked the formation of these products. The present studies suggest
that arachidonic acid is metabolized by 15-lipoxygenase to 15-HPETE,
which undergoes an enzymatic rearrangement to 11-H-14,15-EETA and
15-H-11,12-EETA. Hydrolysis of the epoxy group results in the formation
of 11,14,15- and 11,12,15-THETA, which relaxed rabbit aorta. Thus, the
15-series THETAs join prostacyclin, nitric oxide, and
epoxyeicosatrienoic acids as new members of the family of
endothelium-derived relaxing factors.
Department of Pharmacology and Toxicology,
Medical College of Wisconsin, Milwaukee, Wisconsin 53226 and
§ Department of Biochemistry, University of Texas
Southwestern Medical Center, Dallas, Texas 75235
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