title: Cytochrome P450-derived eicosanoids and vascular dysfunction in coronary artery disease patients.
abstract: OBJECTIVE
  Accumulating preclinical and epidemiologic evidence has emerged to suggest that modulation of cytochrome P450 (CYP)-mediated eicosanoid metabolism may be a viable vascular protective therapeutic strategy for the secondary prevention of coronary artery disease (CAD). The functional relationship between CYP-derived eicosanoid metabolite levels and vascular dysfunction in humans with established CAD, however, has not been evaluated. Therefore, we characterized the relationship between inter-individual variation in soluble epoxide hydrolase (sEH) and CYP ω-hydroxylase metabolism and established vascular function phenotypes predictive of prognosis in a cohort of patients with atherosclerotic cardiovascular disease.
  
  
  METHODS
  Plasma epoxyeicosatrienoic acid (EET), dihydroxyeicosatrienoic acid (DHET), and 20-hydroxyeicosatetraenoic acid (20-HETE) levels were quantified by HPLC-MS/MS in 106 patients with stable, angiographically-confirmed CAD. Relationships between biomarkers of CYP-mediated eicosanoid metabolism and vascular function phenotypes were evaluated by Pearson's correlation.
  
  
  RESULTS
  A significant inverse association was observed between 20-HETE levels (a biomarker of CYP ω-hydroxylase metabolism) and brachial artery flow-mediated dilation (r = -0.255, p = 0.010). An inverse association was also observed between 14,15-EET:DHET ratios (a biomarker of sEH metabolism) and both monocyte chemoattractant protein-1 levels (r = -0.252, p = 0.009) and a consolidated cellular adhesion molecule 'score' reflecting the levels of E-selectin and P-selectin (r = -0.216, p = 0.027). No associations with C-reactive protein or epithelial neutrophil-activating protein-78 levels were observed.
  
  
  CONCLUSIONS
  Collectively, these findings demonstrate that enhanced CYP ω-hydroxylase and sEH metabolic function are associated with more advanced endothelial dysfunction and vascular inflammation, respectively, in patients with established atherosclerotic cardiovascular disease. These findings lay the foundation for future clinical research in this area.
authors: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
authors: Robert N
authors: RN
authors: Schuck
authors: Katherine N
authors: KN
authors: Theken
authors: Matthew L
authors: ML
authors: Edin
authors: Melissa
authors: M
authors: Caughey
authors: Almasa
authors: A
authors: Bass
authors: Kyle
authors: K
authors: Ellis
authors: Bryant
authors: B
authors: Tran
authors: Savanna
authors: S
authors: Steele
authors: Brian P
authors: BP
authors: Simmons
authors: Fred B
authors: FB
authors: Lih
authors: Kenneth B
authors: KB
authors: Tomer
authors: Michael C
authors: MC
authors: Wu
authors: Alan L
authors: AL
authors: Hinderliter
authors: George A
authors: GA
authors: Stouffer
authors: Darryl C
authors: DC
authors: Zeldin
authors: Craig R
authors: CR
authors: Lee
mesh_terms: D000368:Aged; D050197:Atherosclerosis / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood; D003324:Coronary Artery Disease / Q000097:blood* / Q000473:pathology; D003430:Cross-Sectional Studies; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015777:Eicosanoids / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D004851:Epoxide Hydrolases / Q000097:blood; D005260:Female; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000097:blood; D007249:Inflammation; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011379:Prognosis
chemical_list: D015415:Biomarkers; D015777:Eicosanoids; D006893:Hydroxyeicosatetraenoic Acids; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D004851:Epoxide Hydrolases