Beyond vasodilatation: non-vasomotor roles of epoxyeicosatrienoic acids in the cardiovascular system

Epoxyeicosatrienoic acids (EETs), derived from arachidonic acid by cytochrome P450 epoxygenases, are potent vasodilators that function as endothelium-derived hyperpolarizing factors in some vascular beds. EETs are rapidly metabolized by soluble epoxide hydrolase to form dihydroxyeicosatrienoic acids (DHETs). Recent reports indicate that EETs have several important non-vasomotor regulatory roles in the cardiovascular system. EETs are potent anti-inflammatory agents and might function as endogenous anti-atherogenic compounds. In addition, EETs and DHETs might stimulate lipid metabolism and regulate insulin sensitivity. Thus, pharmacological inhibition of soluble epoxide hydrolase might be useful not only for hypertension but also for abating atherosclerosis, diabetes mellitus and the metabolic syndrome. Finally, although usually protective in the systemic circulation, EETs might adversely affect the pulmonary circulation.

Introduction

Arachidonic acid is rapidly oxidized by various oxygenase enzymes to produce several classes of bioactive signaling compounds. Cyclooxygenase and lipoxygenase metabolites of arachidonic acid are now widely recognized as contributing factors in human pathology and are clinically targeted to treat inflammation, cardiovascular disease, asthma and other disorders, but a third major class of arachidonic acid metabolites is attracting considerable attention as a potential therapeutic target for various pathological conditions, especially cardiovascular disease 1, 2, 3.

Cytochrome P450 epoxygenases (CYPs) metabolize arachidonic acid at any one of four double bonds to form four distinct epoxyeicosatrienoic acids, namely 5,6-, 8,9-, 11,12- and 14,15-EET (Figure 1), which together form a group of potent vasodilators with varying degrees of bioactivity [4]. The relative abundance of each EET regioisomer might differ among vascular beds depending on which CYP isoforms are expressed, because each CYP isoform generates its own unique profile of EET regioisomers 5, 6, 7. EETs are rapidly metabolized by soluble epoxide hydrolase (sEH) to form dihydroxyeicosatrienoic acids (DHETs), which are generally less bioactive than their corresponding EETs.

EETs induce vasodilatation through activation of Ca²⁺-activated potassium (K_Ca) channels, and function as endothelium-derived hyperpolarizing factors (EDHFs) in some vascular beds 8, 9, 10, 11, 12. EDHFs are important modulators of vascular tone in cardiovascular disease states 13, 14, 15 when the bioavailability of endothelium-derived vasodilator nitric oxide (NO) is reduced (e.g. by quenching by excess superoxide [16]). EDHFs are particularly important in the microcirculation 13, 17. Unlike the effects of NO, EET-mediated vasodilatation persists in cardiovascular disease 11, 15. In fact, EET bioavailability might be enhanced in cardiovascular disease, because NO-mediated inhibition of CYP is reduced [18]. Indeed, vascular EET synthesis is increased in cholesterol-fed rabbits [19] and is stimulated by atherogenic concentrations of low-density lipoprotein [20].

In addition to the established role of EETs as vasodilators, recent reports suggest that these eicosanoids have several other non-vasomotor regulatory roles in the cardiovascular system. Epidemiological studies suggest that polymorphisms in CYP and sEH might contribute to human cardiovascular disease 21, 22, 23, 24, 25, 26. Because many of the vasculoprotective properties of NO are shared by EETs, these arachidonic acid metabolites might represent endogenous vasculoprotective agents that could be exploited for therapeutic applications [2].

In this review, we outline recent developments and emerging issues in the rapidly expanding field of EETs, and offer new perspective on the potential relevance of these advances in three key areas of clinical translation: atherosclerosis; insulin resistance and the metabolic syndrome; and pulmonary hypertension.