Enhanced synthesis of epoxyeicosatrienoic acids by cholesterol-fed rabbit aorta

S. L. Pfister, J R Falck, W. B. Campbell

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

Arachidonic acid metabolism via cyclooxygenase, lipoxygenase, and cytochrome P-450 epoxygenase was investigated in thoracic aortic tissue obtained from rabbits fed either standard rabbit chow or chow containing 2% cholesterol. Aortic strips were incubated with [14C]arachidonic acid and A23187. Metabolites from extracted media were resolved by high-pressure liquid chromatography (HPLC). Normal and cholesterol-fed rabbit aortas synthesized prostaglandins (PGs) and hydroxyeicosatetraenoic acids (HETEs). The major cyclooxygenase products were 6-keto-PGF(1α) and PGE2. Basal aortic 6-keto-PGF(1α) production was slightly reduced in cholesterol-fed compared with normal rabbits. 12(S)- and 15(S)-HETE were the major aortic lipoxygenase products from both normal and cholesterol-fed rabbits. The structures were confirmed by gas chromatography-mass spectrometry (GC-MS). Only cholesterol-fed rabbit aortas metabolized arachidonic acid via cytochrome P-450 epoxygenase to the epoxyeicosatrienoic acids (EETs). 14,15-, 11,12-, 8,9-, and 5,6-EET were identified based on comigration on HPLC with known 14C-labeled standards and typical mass spectra. Incubation of normal aorta with 14,15-EET decreased the basal synthesis of 6-keto-PGF(1α). The other EETs were without effect. The four EET regioisomers relaxed the norepinephrine-precontracted normal and cholesterol-fed rabbit aorta. The relaxation response to 14,15-EET was greater in aortas from cholesterol-fed rabbits. These studies demonstrate that hypercholesterolemia, before the development of atherosclerosis, alters arachidonic acid metabolism via both the cyclooxygenase and epoxygenase pathways.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume261
Issue number3 30-3
StatePublished - 1991

Fingerprint

Aorta
Cholesterol
Rabbits
Acids
Arachidonic Acid
Prostaglandins F
Prostaglandin-Endoperoxide Synthases
Hydroxyeicosatetraenoic Acids
Lipoxygenase
Cytochrome P-450 Enzyme System
High Pressure Liquid Chromatography
Calcimycin
Hypercholesterolemia
Dinoprostone
Gas Chromatography-Mass Spectrometry
Prostaglandins
Atherosclerosis
Norepinephrine
Thorax

Keywords

  • 6-Ketoprostaglandin F(1α)
  • Antherosclerosis
  • Arachidonic acid
  • Cytochrome P-450

ASJC Scopus subject areas

  • Physiology

Cite this

Enhanced synthesis of epoxyeicosatrienoic acids by cholesterol-fed rabbit aorta. / Pfister, S. L.; Falck, J R; Campbell, W. B.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 261, No. 3 30-3, 1991.

Research output: Contribution to journalArticle

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abstract = "Arachidonic acid metabolism via cyclooxygenase, lipoxygenase, and cytochrome P-450 epoxygenase was investigated in thoracic aortic tissue obtained from rabbits fed either standard rabbit chow or chow containing 2{\%} cholesterol. Aortic strips were incubated with [14C]arachidonic acid and A23187. Metabolites from extracted media were resolved by high-pressure liquid chromatography (HPLC). Normal and cholesterol-fed rabbit aortas synthesized prostaglandins (PGs) and hydroxyeicosatetraenoic acids (HETEs). The major cyclooxygenase products were 6-keto-PGF(1α) and PGE2. Basal aortic 6-keto-PGF(1α) production was slightly reduced in cholesterol-fed compared with normal rabbits. 12(S)- and 15(S)-HETE were the major aortic lipoxygenase products from both normal and cholesterol-fed rabbits. The structures were confirmed by gas chromatography-mass spectrometry (GC-MS). Only cholesterol-fed rabbit aortas metabolized arachidonic acid via cytochrome P-450 epoxygenase to the epoxyeicosatrienoic acids (EETs). 14,15-, 11,12-, 8,9-, and 5,6-EET were identified based on comigration on HPLC with known 14C-labeled standards and typical mass spectra. Incubation of normal aorta with 14,15-EET decreased the basal synthesis of 6-keto-PGF(1α). The other EETs were without effect. The four EET regioisomers relaxed the norepinephrine-precontracted normal and cholesterol-fed rabbit aorta. The relaxation response to 14,15-EET was greater in aortas from cholesterol-fed rabbits. These studies demonstrate that hypercholesterolemia, before the development of atherosclerosis, alters arachidonic acid metabolism via both the cyclooxygenase and epoxygenase pathways.",
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