title: Cytochrome P450-derived epoxyeicosatrienoic acids and coronary artery disease in humans: a targeted metabolomics study.
abstract: Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) exhibit potent cardiovascular protective effects in preclinical models, and promoting the effects of EETs has emerged as a potential therapeutic strategy for coronary artery disease (CAD). The relationship between circulating EET levels and CAD extent in humans, however, remains unknown. A panel of free (unesterified) plasma eicosanoid metabolites was quantified in 162 patients referred for coronary angiography, and associations with extent of CAD [no apparent CAD (N = 39), nonobstructive CAD (N = 51), and obstructive CAD (N = 72)] were evaluated. A significant relationship between free EET levels and CAD extent was observed (P = 0.003) such that the presence of obstructive CAD was associated with lower circulating EET levels. This relationship was confirmed in multiple regression analysis where CAD extent was inversely and significantly associated with EET levels (P = 0.013), and with a biomarker of EET biosynthesis (P < 0.001), independent of clinical and demographic factors. Furthermore, quantitative enrichment analysis revealed that these associations were the most pronounced compared with other eicosanoid metabolism pathways. Collectively, these findings suggest that the presence of obstructive CAD is associated with lower EET metabolite levels secondary to suppressed EET biosynthesis. Novel strategies that promote the effects of EETs may have therapeutic promise for patients with obstructive CAD.
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill Eshelman School of Pharmacy, University of North Carolina at Chapel Hill School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: Akinyemi
authors.initials: A
authors.lastname: Oni-Orisan
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Edin
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill Eshelman School of Pharmacy, University of North Carolina at Chapel Hill School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: John Andrew
authors.initials: JA
authors.lastname: Lee
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill Eshelman School of Pharmacy, University of North Carolina at Chapel Hill School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Wells
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill Eshelman School of Pharmacy, University of North Carolina at Chapel Hill School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: Erin S
authors.initials: ES
authors.lastname: Christensen
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill Eshelman School of Pharmacy, University of North Carolina at Chapel Hill School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Vendrov
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC.
authors.forename: Fred B
authors.initials: FB
authors.lastname: Lih
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC.
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Tomer
authors.affiliation: Department of Pathology and Lab Medicine, University of North Carolina at Chapel Hill School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: Xue
authors.initials: X
authors.lastname: Bai
authors.affiliation: Department of Pathology and Lab Medicine, University of North Carolina at Chapel Hill School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC McAllister Heart Institute, University of North Carolina at Chapel Hill School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: Joan M
authors.initials: JM
authors.lastname: Taylor
authors.affiliation: McAllister Heart Institute, University of North Carolina at Chapel Hill School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC Division of Cardiology, University of North Carolina at Chapel Hill School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: George A
authors.initials: GA
authors.lastname: Stouffer
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC.
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill Eshelman School of Pharmacy, University of North Carolina at Chapel Hill School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC McAllister Heart Institute, University of North Carolina at Chapel Hill School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC craig_lee@unc.edu.
authors.forename: Craig R
authors.initials: CR
authors.lastname: Lee
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000097:blood; D000328:Adult; D000368:Aged; D016718:Arachidonic Acid / Q000378:metabolism*; D001095:Arachidonic Acids / Q000097:blood / Q000378:metabolism*; D015415:Biomarkers / Q000097:blood; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000097:blood / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000097:blood / Q000378:metabolism*; D005260:Female; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000097:blood; D007249:Inflammation / Q000097:blood / Q000378:metabolism; D008297:Male; D055432:Metabolomics; D008875:Middle Aged
chemical_list: D001095:Arachidonic Acids; D015415:Biomarkers; D006893:Hydroxyeicosatetraenoic Acids; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D015126:8,11,14-Eicosatrienoic Acid
keywords: arachidonic acid; atherosclerosis; eicosanoids; heart; inflammation; pharmacometabolomics; precision medicine