Soluble epoxide hydrolase: gene structure, expression and deletion

Abstract

Mammalian soluble epoxide hydrolase (sEH) converts epoxides to their corresponding diols through the addition of a water molecule. sEH readily hydrolyzes lipid signaling molecules, including the epoxyeicosatrienoic acids (EETs), epoxidized lipids produced from arachidonic acid by the action of cytochrome p450s. Through its metabolism of the EETs and other lipid mediators, sEH contributes to the regulation of vascular tone, nociception, angiogenesis and the inflammatory response. Because of its central physiological role in disease states such as cardiac hypertrophy, diabetes, hypertension, and pain sEH is being investigated as a therapeutic target. This review begins with a brief introduction to sEH protein structure and function. sEH evolution and gene structure are then discussed before human small nucleotide polymorphisms and mammalian gene expression are described in the context of several disease models. The review ends with an overview of studies that have employed the sEH knockout mouse model.

Keywords: 20-HETE; 20-hydroxyeicosatetraenoic acid; 5-lipoxygenase activation protein; AP-1; ARIC; ATF-6; Ang-II; Atherosclerosis Risk in Communities; CAC; CARDIA; CPR; ChIP; Coronary Artery Risk Development in Young Adults; DHA; DHETs; EETs; EPA; EPHX2; EpFAs; Epoxyeicosatrienoic acid; FLAP; GSIS; HUVECs; Hcy; Hypertension; IBD; IL-10; Inflammation; LPS; Lipid signaling; NSAID; OVX; PPARs; RAAS; RBC; SHR; SNPs; SP-1; STZ; THF; UPREs; UTR; VSM; WKY; Wistar-Kyoto; activating transcription factor-6; activator protein 1; angiotensin II; cardiopulmonary resuscitation; chromatin immunoprecipitation; coronary artery calcification; dihydroxyeicosatrienoic acids; docosahexaenoic acid; eNOS; eicosapentaenoic acid; endothelial nitric oxide synthase; epoxy-fatty acids; epoxyeicosatrienoic acids; glucose-stimulated insulin secretion; homocysteine; human umbilical vein endothelial cells; inflammatory bowel disease; interleukin-10; lipopolysaccharide; nonsteroidal anti-inflammatory drug; ovariectomized; peroxisome-proliferator activated receptors; red blood cell; renin–angiotensin aldosterone system; sEH; single nucleotide polymorphisms; soluble epoxide hydrolase; specificity protein 1; spontaneously hypertensive rat; streptozotocin; tetrahydrofuran; unfolded protein response elements; untranslated region; vascular smooth muscle.

Figure 1

Crystal structure of the sEH dimer (PDB accession code 1S80 (Gomez et al., 2004).) The sEH monomer is composed of two globular regions displaying alpha/beta fold tertiary structure connected by a short proline-rich linker. The sEH dimer is anti-parallel, so that the N-terminal region of one monomer is in contact with the C-terminal region of the other. The catalytic site for the epoxide hydrolase activity is located within the C-terminal region, while the phosphatase activity is located within the N-terminal region.

Figure 2

Substrates and products of sEH epoxide hydrolase activity. Through the addition of water, sEH converts lipid epoxides to diols (the oxygen of the epoxide moiety is in red). Potential substrates for sEH include the omega-three lipid epoxides formed from DHA and EPA, the omega-six lipid epoxides formed from arachidonic acid (ARA), linoleic acid, and stearic acid. The regioisomers preferred by the human sEH are displayed (Morisseau et al., 2010).

Figure 3

sEH evolution. The mammalian sEH is the product of a gene fusion event and subsequent gene duplication that resulted in two full length sEH genes in S. purpuratus. One of these genes produces a protein with no phosphatase or epoxide hydrolase activity, while the other produces a protein with epoxide hydrolase but no phosphatase activity. In chicken there is a single sEH homolog with epoxide hydrolase but no phosphatase activity. The mammalian sEH in mouse, rat, pig, and human exhibit both epoxide hydrolase and phosphatase activities.

Figure 4

Simplified model of the balance of lipid mediators in the kidney. The vasodilatory epoxyeicosatrienoic acids (EETs—represented by the single isomer 14,15-EET here) are produced from arachidonic acid (ARA) through the action of cytochrome P450s (CYPs) 2J and 2C. This anti-hypertensive signal is offset by a second metabolite of ARA, 20-hydroxyeicosatetraenoic acid (20-HETE) produced by CYP 4A. The balance of antihypertensive and hypertensive signals is partially maintained through the action of sEH. sEH metabolizes the EETs to diol species that are readily conjugated and removed from the site of action in the kidney vasculature. When sEH is inhibited there is an increase in EET levels relative to 20-HETE levels. This tips the balance in favor of vasodilation, creating an anti-hypertensive effect. The process is highly simplified since the epoxy fatty acids and their corresponding diols can be of multiple chain lengths in both the ω-3 and ω-6 series with varying regio, geometrical, and optical isomers involved.