Evaluation of cytochrome P450-derived eicosanoids in humans with stable atherosclerotic cardiovascular disease

Abstract

Objective: Preclinical and genetic epidemiologic studies suggest that modulating cytochrome P450 (CYP)-mediated arachidonic acid metabolism may have therapeutic utility in the management of coronary artery disease (CAD). However, predictors of inter-individual variation in CYP-derived eicosanoid metabolites in CAD patients have not been evaluated to date. Therefore, the primary objective was to identify clinical factors that influence CYP epoxygenase, soluble epoxide hydrolase (sEH), and CYP ω-hydroxylase metabolism in patients with established CAD.

Methods: Plasma levels of epoxyeicosatrienoic acids (EETs), dihydroxyeicosatrienoic acids (DHETs), and 20-hydroxyeicosatetraenoic acid (20-HETE) were quantified by HPLC-MS/MS in a population of patients with stable, angiographically confirmed CAD (N=82) and healthy volunteers from the local community (N=36). Predictors of CYP epoxygenase, sEH, and CYP ω-hydroxylase metabolic function were evaluated by regression.

Results: Obesity was significantly associated with low plasma EET levels and 14,15-EET:14,15-DHET ratios. Age, diabetes, and cigarette smoking also were significantly associated with CYP epoxygenase and sEH metabolic activity, while only renin-angiotensin system inhibitor use was associated with CYP ω-hydroxylase metabolic activity. Compared to healthy volunteers, both obese and non-obese CAD patients had significantly higher plasma EETs (P<0.01) and epoxide:diol ratios (P<0.01), whereas no difference in 20-HETE levels was observed (P=NS).

Conclusions: Collectively, these findings suggest that CYP-mediated eicosanoid metabolism is dysregulated in certain subsets of CAD patients, and demonstrate that biomarkers of CYP epoxygenase and sEH, but not CYP ω-hydroxylase, metabolism are altered in stable CAD patients relative to healthy individuals. Future studies are necessary to determine the therapeutic utility of modulating these pathways in patients with CAD.

Figure 1

Distribution of plasma (A) sum EETs, (B) sum DHETs, (C) 14,15-EET:14,15-DHET, and (D) 20-HETE in healthy volunteers (HV, n=36), non-obese CAD patients (n=36), and obese CAD patients (n=46) plotted on a log₁₀-scale. The line within the box defines the median, the ends of the boxes define the 25^th and 75^th percentiles, the error bars define the 10^th and 90^th percentiles, and the individual points identify values outside the 10^th and 90^th percentiles. *Unadjusted P<0.0125 versus HV. ^†P<0.0125 versus HV after adjusting for age, gender, and race. **P<0.0125 for the obese CAD versus non-obese CAD comparison.