A. Oni-Orisan,1 M. L. Edin,2 J. Lee,1 G. A. Stouffer,3 D. C. Zeldin,2 C. R. Lee1; 1UNC Eshelman School of Pharmacy, Chapel Hill, NC, 2National Institute of Environmental Health Sciences, Research Triangle Park, NC, 3UNC School of Medicine, Chapel Hill, NC
BACKGROUND: CYP2J2 and CYP2C8/9 metabolize arachidonic acid to bioactive epoxyeicosanoids (EETs), which are hydrolyzed by soluble epoxide hydrolase (sEH) into less active diols (DHETs). The EETs have potent vascular protective effects in preclinical models and have emerged as a novel therapeutic target for coronary artery disease (CAD). The relationship between EET levels and CAD severity in humans, however, remains unknown.
METHODS: A cross-sectional study was conducted in 161 patients referred for coronary angiography. Pre-angiography plasma EET and DHET levels were quantified by LC-MS/MS. CAD status was defined as obstructive (≥70% stenosis in ≥1 major coronary artery), non-obstructive (10-70%), and no CAD (<10%). The relationship between EETs, total EETs+DHETs (biomarker of CYP-mediated EET biosynthesis), and 14,15-EET:DHET (biomarker of sEH-mediated EET hydrolysis) and CAD status was evaluated by ANOVA (P<0.05 was significant).
RESULTS: Participants were 62±10 years old, 57% male, and 21% African-American, and 32% and 80% had diabetes and hypertension, respectively. There was an inverse relationship between CAD status (none [n=38] vs. non-obstructive [n=51] vs. obstructive [n=72]) and both EET levels (median [IQR]: 778  vs. 678  vs. 622  pg/mL, P=0.005) and total EET+DHET levels (2975  vs. 2494  vs. 2346  pg/mL, P=0.001). Similar results were obtained following covariate adjustment. In contrast, no relationship with 14,15-EET:DHET was observed (P=0.711).
CONCLUSION: Increasing CAD severity was associated with significantly lower EET levels secondary to decreased EET biosynthesis and not increased EET hydrolysis. Future studies evaluating CYP-derived EETs as a pharmacologic target for CAD are warranted.