Functional implications of a newly characterized pathway of 11,12- epoxyeicosatrienoic acid metabolism in arterial smooth muscle

Xiang Fang, Terry L. Kaduce, Neal L. Weintraub, Mike VanRollins, Arthur A. Spector

Research output: Contribution to journalArticle

88 Scopus citations

Abstract

Epoxyeicosatrienoic acids (EETs) are potent vasodilators derived from cytochrome P-450 metabolism of arachidonic acid. The rapid conversion of EETs to their corresponding dihydroxyeicosatrienoic acids (DHETs) has been proposed as a process whereby EETs are rendered biologically inactive. However, the vascular metabolism of EETs and the vasoactivities of EET metabolites have not been extensively studied. Accordingly, 11.12-EET metabolism was characterized in porcine aortic smooth muscle cells. The cells converted [ 3 H]11.12-EET to 11,12-DHET and to a newly identified metabolite, 7,8-dihydroxy-hexadecadienoic acid (DHHD), 11,12-DHET accumulation in the medium reached a maximum in 2 to 4 hours and then declined, whereas 7,8-DHHD accumulation increased continuously and exceeded the amount of 11,12-DHET by 8 hours. [ 3 H] 11.12-EET conversion to radiolabeled 7.8-DHHD was reduced in the presence of unlabeled 11,12-DHET, indicating that 11,12-DHET is an intermediate in the conversion of 11,12-EET to 7,8-DHHD. This is consistent with a pathway whereby 11,12 EET is convened by an epoxide hydrolase to 11,12-DHET, which then undergoes two β-oxidations to form 7,8 DHHD. In porcine coronary artery rings contracted with a thromboxane mimetic, 11,12- DHET produced relaxation similar in magnitude to that produced by 11,12-EET (77% versus 64% relaxation at 5 μmol/L, respectively), 7,8-DHHD also produced vasorelaxation. Thus, the vasoactivity of 11,12-EET is not eliminated by conversion to 11,12-DHET and 7,8-DHHD. These results suggest that 11,12-DHET and its metabolite, 7,8-DHHD, may contribute to the regulation of vascular tone in the porcine coronary artery and possibly other vascular tissues.

Original languageEnglish (US)
Pages (from-to)784-793
Number of pages10
JournalCirculation Research
Volume79
Issue number4
DOIs
StatePublished - Jan 1 1996
Externally publishedYes

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Keywords

  • cytochrome P-450
  • dihydroxyeicosatrienoic acid
  • epoxyeicosatrienoic acid
  • porcine aortic smooth muscle cell
  • porcine coronary artery

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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