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The role of epoxyeicosatrienoic acids in the cardiovascular system.

ABSTRACT: There is increasing evidence suggesting that epoxyeicosatrienoic acids (EETs) play an important role in cardioprotective mechanisms. These include regulating vascular tone, modulating inflammatory responses, improving cardiomyocyte function and reducing ischaemic damage, resulting in attenuation of animal models of cardiovascular risk factors. This review discusses the current knowledge on the role of EETs in endothelium-dependent control of vascular tone in the healthy and in subjects with cardiovascular risk factors, and considers the pharmacological potential of targeting this pathway.

SUBMITTER: Yang L

PROVIDER: S-EPMC4500322 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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The role of epoxyeicosatrienoic acids in the cardiovascular system.

Yang L L Mäki-Petäjä K K Cheriyan J J McEniery C C Wilkinson I B IB

British journal of clinical pharmacology 20150601 1

There is increasing evidence suggesting that epoxyeicosatrienoic acids (EETs) play an important role in cardioprotective mechanisms. These include regulating vascular tone, modulating inflammatory responses, improving cardiomyocyte function and reducing ischaemic damage, resulting in attenuation of animal models of cardiovascular risk factors. This review discusses the current knowledge on the role of EETs in endothelium-dependent control of vascular tone in the healthy and in subjects with card ...[more]

PMID: 25655310

Similar Datasets

Inside epoxyeicosatrienoic acids and cardiovascular disease.

Project description:Epoxyeicosatrienoic acids (EETs) generated from arachidonic acid through cytochrome P450 (CYP) epoxygenases have many biological functions. Importantly, CYP epoxygenase-derived EETs are involved in the maintenance of cardiovascular homeostasis. In fact, in addition to their potent vasodilating effect, EETs have potent anti-inflammatory properties, inhibit platelet aggregation, promote fibrinolysis, and reduce vascular smooth muscle cell proliferation. All EETs are metabolized to the less active dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH). Numerous evidences support the role of altered EET biosynthesis in the pathophysiology of hypertension and suggest the utility of antihypertensive strategies that increase CYP-derived EET or EET analogs. Indeed, a number of studies have demonstrated that EET analogs and sEH inhibitors induce vasodilation, lower blood pressure and decrease inflammation. Some of these agents are currently under evaluation in clinical trials for treatment of hypertension and diabetes. However, the role of CYP epoxygenases and of the metabolites generated in cancer progression may limit the use of these drugs in humans.

| S-EPMC4226225 | biostudies-literature

Plasma epoxyeicosatrienoic acids and diabetes-related cardiovascular disease: The cardiovascular health study.

Project description:BackgroundEpoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid that may impact atherosclerosis, and animal experimental studies suggest EETs protect cardiac function. Plasma EETs are mostly esterified to phospholipids and part of an active pool. To address the limited information about EETs and CVD in humans, we conducted a prospective study of total plasma EETs (free + esterified) and diabetes-related CVD in the Cardiovascular Health Study (CHS).MethodsWe measured 4 EET species and their metabolites, dihydroxyepoxyeicosatrienoic acids (DHETs), in plasma samples from 892 CHS participants with type 2 diabetes. We determined the association of EETs and DHETs with incident myocardial infarction (MI) and ischemic stroke using Cox regression.FindingsDuring follow-up (median 7.5 years), we identified 150 MI and 134 ischemic strokes. In primary, multivariable analyses, elevated levels of each EET species were associated with non-significant lower risk of incident MI (for example, hazard ratio for 1 SD higher 14,15-EET: 0.86, 95% CI: 0.72-1.02; p=0.08). The EETs-MI associations became significant in analyses further adjusted for DHETs (hazard ratio for 1 SD higher 14,15-EET adjusted for 14,15-DHET: 0.76, 95% CI: 0.63-0.91; p=0.004). Elevated EET levels were associated with higher risk of ischemic stroke in primary but not secondary analyses. Three DHET species were associated with higher risk of ischemic stroke in all analyses.InterpretationFindings from this prospective study complement the extensive studies in animal models showing EETs protect cardiac function and provide new information in humans. Replication is needed to confirm the associations.FundingUS National Institutes of Health.

| S-EPMC9356248 | biostudies-literature

Cyclooxygenase-derived proangiogenic metabolites of epoxyeicosatrienoic acids.

Project description:Arachidonic acid (ARA) is metabolized by cyclooxygenase (COX) and cytochrome P450 to produce proangiogenic metabolites. Specifically, epoxyeicosatrienoic acids (EETs) produced from the P450 pathway are angiogenic, inducing cancer tumor growth. A previous study showed that inhibiting soluble epoxide hydrolase (sEH) increased EET concentration and mildly promoted tumor growth. However, inhibiting both sEH and COX led to a dramatic decrease in tumor growth, suggesting that the contribution of EETs to angiogenesis and subsequent tumor growth may be attributed to downstream metabolites formed by COX. This study explores the fate of EETs with COX, the angiogenic activity of the primary metabolites formed, and their subsequent hydrolysis by sEH and microsomal EH. Three EET regioisomers were found to be substrates for COX, based on oxygen consumption and product formation. EET substrate preference for both COX-1 and COX-2 were estimated as 8,9-EET > 5,6-EET > 11,12-EET, whereas 14,15-EET was inactive. The structure of two major products formed from 8,9-EET in this COX pathway were confirmed by chemical synthesis: ct-8,9-epoxy-11-hydroxy-eicosatrienoic acid (ct-8,9-E-11-HET) and ct-8,9-epoxy-15-hydroxy-eicosatrienoic acid (ct-8,9-E-15-HET). ct-8,9-E-11-HET and ct-8,9-E-15-HET are further metabolized by sEH, with ct-8,9-E-11-HET being hydrolyzed much more slowly. Using an s.c. Matrigel assay, we showed that ct-8,9-E-11-HET is proangiogenic, whereas ct-8,9-E-15-HET is not active. This study identifies a functional link between EETs and COX and identifies ct-8,9-E-11-HET as an angiogenic lipid, suggesting a physiological role for COX metabolites of EETs.

| S-EPMC5410821 | biostudies-literature

Effects of angiotensin II receptor blockers on serum levels of epoxyeicosatrienoic acids and dihydroxyeicosatrienoic acids in patients admitted to a cardiovascular center.

Project description:PurposeSeveral clinical studies have demonstrated that angiotensin-converting enzyme inhibitors, but not angiotensin II receptor blockers (ARBs), reduce the risk of non-fatal myocardial infarction and cardiovascular mortality. We found that ARBs inhibited the activity of various cytochrome enzymes in arachidonic acid metabolism, resulting in decreased in vitro production of epoxyeicosatrienoic acids (EETs), which exhibit vasodilation and anti-inflammatory effects, and their subsequent metabolites, dihydroxyeicosatrienoic acids (DHETs). The present study examined the effects of ARBs on serum levels of EETs and DHETs in patients admitted to a cardiovascular center.MethodsA total of 223 patients were enrolled, of which 107 were exposed to ARBs in this study. ARB-free individuals were defined as the control group (n = 116). Serum levels of EETs and DHETs were measured by liquid chromatography-tandem mass spectrometry. Multiple linear regression analyses were carried out to identify covariates for total serum levels of EETs and DHETs.ResultsA significant negative association was observed between ARB use and serum EET and DHET levels (p = 0.034), whereas a significant positive association was observed between the estimated glomerular filtration rate (eGFR) and serum EET and DHET levels (p = 0.007). The median serum total EET and DHET level in the ARB group tended to become lower than that in the control group, although the difference was not significant.ConclusionARB use and eGFR were significantly associated with total serum levels of EETs and DHETs. Our results suggest that ARBs could affect the concentration of EETs in vivo.

| S-EPMC8128744 | biostudies-literature

The Role of Cytochrome P450 Epoxygenases, Soluble Epoxide Hydrolase, and Epoxyeicosatrienoic Acids in Metabolic Diseases.

Project description:Metabolic diseases are associated with an increased risk of developing cardiovascular disease. The features comprising metabolic diseases include obesity, insulin resistance, hyperglycemia, hyperlipidemia, and hypertension. Recent evidence has emerged showcasing a role for cytochrome P450 epoxygenases, soluble epoxide hydrolase, and epoxyeicosatrienoic acids (EETs) in the development and progression of metabolic diseases. This review discusses the current knowledge related to the modulation of cytochrome P450 epoxygenases and soluble epoxide hydrolase to alter concentrations of biologically active EETs, resulting in effects on insulin resistance, lipid metabolism, obesity, and diabetes. Future areas of research to address current deficiencies in the understanding of these enzymes and their eicosanoid metabolites in various aspects of metabolic diseases are also discussed.

| S-EPMC5105036 | biostudies-literature

Epoxyeicosatrienoic Acids Enhance Haematopoietic Stem and Progenitor Cell Specification and Engraftment

Project description:Haematopoietic stem and progenitor cell (HSPC) transplant is a widely used treatment for life-threatening conditions including leukemia; however, the molecular mechanisms regulating HSPC engraftment of the recipient niche remain incompletely understood. Here, we developed a competitive HSPC transplant method in adult zebrafish, using in vivo imaging as a non-invasive readout. We used this system to conduct a chemical screen and identified epoxyeicosatrienoic acids (EET) as a family of lipids that enhance HSPC engraftment. EETs’ pro-haematopoietic effects are conserved in the developing zebrafish, where this molecule promotes HSPC specification through activating a unique AP-1/runx1 transcription program autonomous to the haemogenic endothelium. This effect requires the activation of PI3K pathway, specifically PI3Kg. In adult HSPCs, EETs induce transcriptional programs including AP-1 activation, modulating multiple cellular processes, such as migration, to promote engraftment. Finally, we demonstrated that the EET effects on enhancing HSPC homing and engraftment are conserved in mammals. Our study established a novel method to explore the molecular mechanisms of HSPC engraftment, and discovered a previously unrecognized, evolutionarily conserved pathway regulating multiple haematopoietic generation and regeneration processes. EETs may have clinical application in marrow or cord blood transplantation.

2015-07-13 | GSE66767 | GEO

Treatment of Primary Aldosteronism Increases Plasma Epoxyeicosatrienoic Acids.

Project description:[Figure: see text].

| S-EPMC8320355 | biostudies-literature

Impact of epoxyeicosatrienoic acids in lung ischemia-reperfusion injury.

Project description:Epoxyeicosatrienoic acids (EETs) are protective in both myocardial and brain ischemia, variously attributed to activation of K(ATP) channels or blockade of adhesion molecule upregulation. In this study, we tested whether EETs would be protective in lung ischemia-reperfusion injury.The filtration coefficient (K(f)), a measure of endothelial permeability, and expression of the adhesion molecules vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) were measured after 45 minutes ischemia and 30 minutes reperfusion in isolated rat lungs.K(f) increased significantly after ischemia-reperfusion alone vs time controls, an effect dependent upon extracellular Ca(2+) although not on the EET-regulated channel TRPV4. Inhibition of endogenous EET degradation or administration of exogenous 11,12- or 14,-15-EET at reperfusion significantly limited the permeability response to ischemia-reperfusion. The beneficial effect of 11,12-EET was not prevented by blockade of K(ATP) channels nor by blockade of TRPV4. Finally, 11,12-EET-dependent alteration in adhesion molecules expression is unlikely to explain its beneficial effect, since the expression of the adhesion molecules VCAM and ICAM in lung after ischemia-reperfusion was similar to that in controls.EETs are beneficial in the setting of lung ischemia-reperfusion, when administered at reperfusion. However, further study will be needed to elucidate the mechanism of action.

| S-EPMC2923642 | biostudies-literature

Epoxyeicosatrienoic acids enhance embryonic haematopoiesis and adult marrow engraftment.

Project description:Haematopoietic stem and progenitor cell (HSPC) transplant is a widely used treatment for life-threatening conditions such as leukaemia; however, the molecular mechanisms regulating HSPC engraftment of the recipient niche remain incompletely understood. Here we develop a competitive HSPC transplant method in adult zebrafish, using in vivo imaging as a non-invasive readout. We use this system to conduct a chemical screen, and identify epoxyeicosatrienoic acids (EETs) as a family of lipids that enhance HSPC engraftment. The pro-haematopoietic effects of EETs were conserved in the developing zebrafish embryo, where 11,12-EET promoted HSPC specification by activating a unique activator protein 1 (AP-1) and runx1 transcription program autonomous to the haemogenic endothelium. This effect required the activation of the phosphatidylinositol-3-OH kinase (PI(3)K) pathway, specifically PI(3)Kγ. In adult HSPCs, 11,12-EET induced transcriptional programs, including AP-1 activation, which modulate several cellular processes, such as migration, to promote engraftment. Furthermore, we demonstrate that the EET effects on enhancing HSPC homing and engraftment are conserved in mammals. Our study establishes a new method to explore the molecular mechanisms of HSPC engraftment, and discovers a previously unrecognized, evolutionarily conserved pathway regulating multiple haematopoietic generation and regeneration processes. EETs may have clinical application in marrow or cord blood transplantation.

| S-EPMC4754787 | biostudies-literature

Maternal and fetal epoxyeicosatrienoic acids in normotensive and preeclamptic pregnancies.

Project description:BackgroundEpoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE) are cytochrome P450 metabolites of arachidonic acid posited to act in the circulatory adaptation to pregnancy and the development of preeclampsia. Red blood cells (RBCs) may function as major contributors of cis- and trans-EETs.MethodsWe performed paired analyses of EETs, dihydroxyeicosatrienoic acids (DHETs), and 20-HETE in RBCs, plasma, and urine from preeclamptic and normotensive pregnant and nonpregnant women. Blood from fetal and maternal circulation was collected. EETs, DHETs, and 20-HETE were analyzed by gas chromatography and liquid chromatography mass spectrometry. Vascular function and inflammation indices were analyzed.ResultsPlasma EET is higher in normotensive (median, range; 9.9, 6.3-25.2ng/mL n = 29) and preeclamptic (10.9, 6.0-48.0ng/mL, n = 19) women than in nonpregnant controls (7.3, 3.7-10.2ng/mL, n = 19) and correlate with RBC EETs, C-reactive protein, and arterial stiffness. Renal production of EETs, measured as urinary DHETs, was reduced in preeclamptic (4.5, 1.6-24.5ng/mg creatinine) compared to normotensive (11.4, 1.6-44.5ng/mg creatinine) pregnancies. EETs are 3- to 5-fold greater in fetoplacental than in maternal circulation (RBCs 36.6, 13.1-69.4 vs. 12.5, 6.4-12.0ng/10(9) cells; plasma 31.6, 8.5-192.6 vs. 12.0, 6.8-48.0ng/mL). Both cis- and trans-EETs are present in fetal RBCs.ConclusionsRBCs contribute to elevated levels of EETs in the fetoplacental circulation. EETs may modulate systemic and fetoplacental hemodynamics in normal and preeclamptic pregnancies. Decreased renal EET generation may be associated with the development of maternal renal dysfunction and hypertension in preeclampsia.

| S-EPMC3935001 | biostudies-literature

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