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

ABSTRACT: Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) exhibit potent cardiovascular protective effects in preclinical models, and promoting the effects of EETs has emerged as a potential therapeutic strategy for coronary artery disease (CAD). The relationship between circulating EET levels and CAD extent in humans, however, remains unknown. A panel of free (unesterified) plasma eicosanoid metabolites was quantified in 162 patients referred for coronary angiography, and associations with extent of CAD [no apparent CAD (N = 39), nonobstructive CAD (N = 51), and obstructive CAD (N = 72)] were evaluated. A significant relationship between free EET levels and CAD extent was observed (P = 0.003) such that the presence of obstructive CAD was associated with lower circulating EET levels. This relationship was confirmed in multiple regression analysis where CAD extent was inversely and significantly associated with EET levels (P = 0.013), and with a biomarker of EET biosynthesis (P < 0.001), independent of clinical and demographic factors. Furthermore, quantitative enrichment analysis revealed that these associations were the most pronounced compared with other eicosanoid metabolism pathways. Collectively, these findings suggest that the presence of obstructive CAD is associated with lower EET metabolite levels secondary to suppressed EET biosynthesis. Novel strategies that promote the effects of EETs may have therapeutic promise for patients with obstructive CAD.

SUBMITTER: Oni-Orisan A

PROVIDER: S-EPMC4689337 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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

Oni-Orisan Akinyemi A Edin Matthew L ML Lee John Andrew JA Wells Michael A MA Christensen Erin S ES Vendrov Kimberly C KC Lih Fred B FB Tomer Kenneth B KB Bai Xue X Taylor Joan M JM Stouffer George A GA Zeldin Darryl C DC Lee Craig R CR

Journal of lipid research 20151110 1

Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) exhibit potent cardiovascular protective effects in preclinical models, and promoting the effects of EETs has emerged as a potential therapeutic strategy for coronary artery disease (CAD). The relationship between circulating EET levels and CAD extent in humans, however, remains unknown. A panel of free (unesterified) plasma eicosanoid metabolites was quantified in 162 patients referred for coronary angiography, and associations with ...[more]

PMID: 26555503

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Project description:Aims/hypothesisInsulin resistance is frequently associated with hypertension and type 2 diabetes. The cytochrome P450 (CYP) arachidonic acid epoxygenases (CYP2C, CYP2J) and their epoxyeicosatrienoic acid (EET) products lower blood pressure and may also improve glucose homeostasis. However, the direct contribution of endogenous EET production on insulin sensitivity has not been previously investigated. In this study, we tested the hypothesis that endogenous CYP2C-derived EETs alter insulin sensitivity by analysing mice lacking CYP2C44, a major EET producing enzyme, and by testing the association of plasma EETs with insulin sensitivity in humans.MethodsWe assessed insulin sensitivity in wild-type (WT) and Cyp2c44 -/- mice using hyperinsulinaemic-euglycaemic clamps and isolated skeletal muscle. Insulin secretory function was assessed using hyperglycaemic clamps and isolated islets. Vascular function was tested in isolated perfused mesenteric vessels. Insulin sensitivity and secretion were assessed in humans using frequently sampled intravenous glucose tolerance tests and plasma EETs were measured by mass spectrometry.ResultsCyp2c44 -/- mice showed decreased glucose tolerance (639 ± 39.5 vs 808 ± 37.7 mmol/l × min for glucose tolerance tests, p = 0.004) and insulin sensitivity compared with WT controls (hyperinsulinaemic clamp glucose infusion rate average during terminal 30 min 0.22 ± 0.02 vs 0.33 ± 0.01 mmol kg-1 min-1 in WT and Cyp2c44 -/- mice respectively, p = 0.003). Although glucose uptake was diminished in Cyp2c44 -/- mice in vivo (gastrocnemius Rg 16.4 ± 2.0 vs 6.2 ± 1.7 μmol 100 g-1 min-1, p < 0.01) insulin-stimulated glucose uptake was unchanged ex vivo in isolated skeletal muscle. Capillary density was similar but vascular KATP-induced relaxation was impaired in isolated Cyp2c44 -/- vessels (maximal response 39.3 ± 6.5% of control, p < 0.001), suggesting that impaired vascular reactivity produces impaired insulin sensitivity in vivo. Similarly, plasma EETs positively correlated with insulin sensitivity in human participants.Conclusions/interpretationCYP2C-derived EETs contribute to insulin sensitivity in mice and in humans. Interventions to increase circulating EETs in humans could provide a novel approach to improve insulin sensitivity and treat hypertension.

Project description: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 ?-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 ?-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 ?-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.

Dataset Information

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

Publications

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

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