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.

Cytochrome P450-derived epoxyeicosatrienoic acids and coronary artery disease in humans: a targeted metabolomics study

“…protein 1 (MCP-1) concentrations [a proinfl ammatory chemokine predictive of poor prognosis in CAD ( 43 )], in which patients with stable CAD in the lowest and middle EET tertiles had signifi cantly higher MCP-1 levels compared with those in the highest EET tertile ( 18 ). These preliminary observations underscore the need to rigorously evaluate the relationship between EET levels and the risk of cardiovascular events in larger populations.…”

“…The sum EETs served as the primary end point for comparison across CAD extent. The sum of the EET and DHET regioisomers (sum EETs + DHETs) and the ratio of 14,15-EET to 14,15-DHET (14,15-EET:14,15-DHET ratio) (secondary end points) were calculated as biomarkers of CYP epoxygenase and sEH metabolic function, respectively ( 18 ).…”

20-HETE induces remodeling of renal resistance arteries independent of blood pressure elevation in hypertension

“…Several clinical studies (36,37) have shown increased 20-HETE levels in hypertensive individuals. A recent study by Schuck et al (27) demonstrated that enhanced plasma levels of 20-HETE are associated with more advanced endothelial dysfunction and vascular inflammation in patients with established atherosclerotic cardiovascular disease. The proinflammatory and progrowth bioactions of 20-HETE in vascular cells together with its increased occurrence in hypertensive patients suggest that it may play a role in microvascular remodeling and contributes to the development and cardiovascular complications of hypertension.…”

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.…”