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.

Functional characterization of cytochrome P450-derived epoxyeicosatrienoic acids in adipogenesis and obesity

“…We recently reported that obesity was associated with signifi cantly lower circulating EET levels in humans with established cardiovascular disease ( 26 ). Although prior studies have demonstrated that experimental induction of obesity reduces EETs in liver, kidney, and mesenteric arteries ( 21,31 ), as well as alters cyclooxygenase-mediated prostaglandin biosynthesis and lipoxygenase-mediated leukotriene biosynthesis in adipose tissue ( 32,33 ), the impact of obesity on EET bioavailability in adipose tissue has not been rigorously investigated .…”

“…The residue was reconstituted in 30% ethanol, and EET and DHET concentrations were quantifi ed by HPLC-MS/MS. The 14,15-EET:14,15-DHET ratio was calculated as a biomarker of sEH metabolic activity ( 26 ).…”

Effects of Angiotensin II Receptor Blockers on Metabolism of Arachidonic Acid <i>via</i> CYP2C8

“…[26][27][28] The hyperpolarization of smooth muscles and vasodilation induced by EETs are mediated by activation of Ca 2+ -dependent K + channels, with stronger cardioprotection leading to activation of K(ATP) channels. 29) Considering that EET concentrations and the 14,15-EET/14,15-DHET ratio in plasma have negative correlations with the risk of cardiovascular events, 30,31) a decrease of the EETs concentration in patients taking ARBs would correlate with an increase risk of cardiovascular events including sudden cardiac death and myocardial infarction.…”

Oxylipid Profile of Low‐Dose Aspirin Exposure: A Pharmacometabolomics Study

“…Aberrant oxylipid signaling has been shown to lead to a number of pathologies important to cardiovascular disease including hyperlipidemia, hypertension, thrombosis, and hemostasis 13. For example, coronary artery disease patients have higher plasma levels of CYP‐mediated AA metabolites (namely, the oxylipids epoxyeicosatrienoic acid) 14. While some studies have described the effects of aspirin on individual oxylipids,15, 16, 17 to our knowledge, the systematic effect of aspirin on oxylipid as a class has not been described.…”