Possible Role of CYP450 Generated Omega-3/Omega-6 PUFA Metabolites in the Modulation of Blood Pressure and Vascular Function in Obese Children

Abstract

Obesity is often accompanied by metabolic and haemodynamic disorders such as hypertension, even during childhood. Arachidonic acid (AA) is metabolized by cytochrome P450 (CYP450) enzymes to epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE), vasoactive and natriuretic metabolites that contribute to blood pressure (BP) regulation. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) omega-3 polyunsaturated fatty acids may compete with AA for CYP450-dependent bioactive lipid mediator formation. We aimed at investigating the role of AA, EPA and DHA and their CYP450-dependent metabolites in BP control and vascular function in 66 overweight/obese children. Fatty acid profile moderately correlated with the corresponding CYP450-derived metabolites but their levels did not differ between children with normal BP (NBP) and high BP (HBP), except for higher EPA-derived epoxyeicosatetraenoic acids (EEQs) and their diols in HBP group, in which also the estimated CYP450-epoxygenase activity was higher. In the HBP group, EPA inversely correlated with BP, EEQs inversely correlated both with systolic BP and carotid Intima-Media Thickness (cIMT). The DHA-derived epoxydocosapentaenoic acids (EDPs) were inversely correlated with diastolic BP. Omega-3 derived epoxymetabolites appeared beneficially associated with BP and vascular structure/function only in obese children with HBP. Further investigations are needed to clarify the role of omega-3/omega-6 epoxymetabolites in children's hemodynamics.

Keywords: CYP450 eicosanoids; EEQs; EETs; blood pressure; children; hemodynamics; omega-3 PUFA; omega-6 PUFA.

Figure 1

Comparison of fatty acids and their metabolites via CYP450-epoxygenase in HBP and NBP obese children. The histograms represent the comparison between HBP and NBP obese children for: (a) concentration of fatty acids in red blood cell membranes, that is, LA, AA, EPA and DHA; (b) plasma concentration of the CYP450 epoxygenase generated metabolites, that is, EpOMEs, EETs, EEQs and EDPs; (c) the estimated CYP450 epoxygenase activity, calculated as the sum of epoxymetabolites plus their corresponding diols; (d) the estimated sEH activity, calculated as the ratio between plasma concentrations (ng/mL) of diols and epoxymetabolites. Data are presented as mean and SEM. LA: Linoleic acid; AA: Arachidonic acid; EPA: Eicosapentaenoic acid; DHA: Docosahexaenoic acid; EpOME: epoxyoctadecenoic acid; DiHOME: dihydroxyoctadecenoic acid; EET: epoxyeicosatrienoic acid; DHET: dihydroxyeicosatrienoic acid; EEQ: epoxyeicosatetraenoic acid; DiHETE: dihydroxyeicosatetraenoic acid; EDP: epoxydocosapentaenoic acid; DiHDPA: dihydroxydocosapentaenoic acid; HBP: high blood pressure subgroup; NBP: normal blood pressure subgroup; sEH: soluble epoxide hydrolase; p: p-value. Vertical lines represent the standard errors.

Figure 2

Correlations between fatty acids and their metabolite via CYP450-epoxygenase. The graphs represent the correlations of the fatty acids with their corresponding epoxymetabolites. The two subgroups of obese children with high (HBP) and normal blood pressure (NBP) are differently graphically depicted. The panels represent: (a) the correlation of LA with EpOMEs, which was stronger in HBP children; (b) the association of AA with EETs; (c) the correlation of EPA with EEQs, which was stronger in HBP children; (d) the association of DHA with EDPs. LA: Linoleic acid; AA: Arachidonic acid; EPA: Eicosapentaenoic acid; DHA: Docosahexaenoic acid; EpOME: epoxyoctadecenoic acid; EET: epoxyeicosatrienoic acid; EEQ: epoxyeicosatetraenoic acid; EDP:epoxydocosapentaenoic acid; HBP: high blood pressure subgroup; NBP: normal blood pressure subgroup, p: p-value; r_S: Spearman correlation coefficient; n.s.: not significant.

Figure 3

Correlations of EEQ with BP and cIMT in the high blood pressure (HBP) and normal blood pressure (NBP) obese children subgroups. The first column represents the correlation of 17,18-EEQ with: (a) office SBP; (b) night-time SBP; (c) cIMT. The second column represents the correlation of the estimated CYP450 epoxygenase activity, as calculated as the sum of epoxymetabolites plus the corresponding diols, with: (d) office SBP; (e) night-time SBP; (f) cIMT. * there is a significantly difference between the slopes of the two subgroups, p < 0.05. The correlations in all panels are stronger in HBP than in NBP children. The two subgroups of obese children with high and normal blood pressure are differently graphically depicted. cIMT: carotid intima-media thickness; EEQ: epoxyeicosatetraenoic acid; DiHETE: dihydroxyeicosatetraenoic acid; HBP: high blood pressure subgroup; NBP: normal blood pressure subgroup; SBP: systolic blood pressure, p: p-value; r_S: Spearman correlation coefficient.