title: Epoxyeicosatrienoic acid pathway in human health and diseases.
abstract: In response to endothelial cell activation, arachidonic acid can be converted by cytochrome P450 (CYP) epoxygenases to epoxyeicosatrienoic acids (EETs), which have potent vasodilator and anti-inflammatory properties. EETs are rapidly degraded in vivo to the less active dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). Since the beginning of the 2000s, the role of EET pathway in human health and its alteration in diseases has been shown by measuring EETs/DHET levels in blood, by evaluating the relationship between CYP/sEH gene polymorphisms, which modify enzyme activity and thus EETs/DHET level, and by assessing the inhibitory effect of the local administration of CYP epoxygenase inhibitor on endothelium-dependent dilatation. By combining these functional and biological approaches, we demonstrated that EETs are the endothelial factors released by CYP epoxygenases involved in the flow-mediated dilatation of conduit arteries in healthy subjects, together with the impairment of EET availability in essential hypertensive patients at this level. The modulation of EET pathway now emerges as a new promising pharmacological target that may improve the clinical management of patients at high cardiovascular risk. In this respect, the restoration of EET availability using a new class of agents, the inhibitors of sEH, gave promising results in various animal models of cardiovascular diseases, reducing blood pressure and target organ damage, and a first product has entered clinical evaluation.
authors.affiliation: Department of Pharmacology, Rouen University Hospital, Rouen, France. jeremy.bellien@chu-rouen.fr
authors.forename: Jeremy
authors.initials: J
authors.lastname: Bellien
authors.forename: Robinson
authors.initials: R
authors.lastname: Joannides
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D003324:Coronary Artery Disease / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D015777:Eicosanoids / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D043925:Angiogenesis Inducing Agents; D000959:Antihypertensive Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D015777:Eicosanoids; D004791:Enzyme Inhibitors; C400322:cytochrome P-450 CYP2C subfamily; D003577:Cytochrome P-450 Enzyme System; D004851:Epoxide Hydrolases; C506428:EPHX2 protein, human