Soluble epoxide hydrolase: a new target for cardioprotection

Abstract

Arachidonic acid is metabolized to a number of bioactive eicosanoid molecules by several enzymes, including enzymes of the COX, lipoxygenase and cytochrome P450 (CYP) monooxygenase pathways. Inhibition of the CYP omega-hydroxylase pathway, stimulation of the CYP-epoxygenase pathway and administration of exogenous epoxyeicosatrienoic acids resulted in cardioprotection in animal models of ischemia; contractile function was improved in mouse hearts subjected to global ischemia/reperfusion, and infarct size was reduced in canine and rat hearts. Cardioprotective effects were also achieved when metabolism of the endogenous epoxyeicosatrienoic acids (EETs) by their major enzymatic hydrolysis pathway was blocked in gene knockout mice (EPHX2-/-) or by inhibitors of soluble epoxide hydrolase (sEH), such as 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA). Pretreatment of canine hearts with AUDA dose-dependently reduced infarct size, and AUDA enhanced the infarct-sparing effect of treatment with exogenous EETs. The preliminary results of studies in rodent hearts have also demonstrated that AUDA and AUDA-butyl ester reduce infarct size. These results and others obtained in models of myocardial stunning and hypertrophy suggest that inhibitors of EPHX2 or sEH have therapeutic potential in a broad range of cardiovascular diseases.

Figure 1. Mechanistic pathways of soluble epoxide hydrolase inhibitors and/or epoxyeicosatrienoic acids in cardioprotection

Several potential pathways for the activity of soluble epoxide hydrolase (sEH) inhibitors have been identified that may be involved in epoxyeicosatrienoic acid (EET)-induced cardioprotection. Because there is evidence that the EETs may exert both extracellular and intracellular effects, it is postulated that there may be an EET receptor (EETR) at the cell surface or within the mitochondria; however, no EET receptor has been cloned and this hypothesis remains questionable. 2MPG 2-mercaptopropionyl glycine, 5-HD 5-hydroxydecanoic acid, 14,15-EEZE 14,15-epoxyeicosa-5(Z)-enoic acid, AUDA .12-(3-adamantan-1-yt-ureido) dodecanoic acid, cPLA₂ cytosolic phosphotipase A₂, CYP Epox cytochrome P-450 epoxygenase, DHETs dihydroxyeicosatrienoic acids, mitoK_ATP mitochondrial ATP-sensitive potassium channel, mPTP mitochondrial permeabitity transitionpore, p-Akt phosphorylated Akt, p-GSK3β phospho-gtycogen synthase kinase-3β, Pl3K phosphoinositol-3-kinase, ROS reactive oxygen species, SarcK_ATP sarcolemmal ATP-sensitive potassium channel

Figure 2. The effects of AUDA and 14,15-EET on myocardial infarct size

Effects of Low-dose (LD; 0.157 mg/kg) and high-dose (HD; 0.3,l4 mg/kg) l2-(3-adamantan-l-yl-ureido) dodecanoic acid (AUDA), and 14,15-epoxyeicosatrienoic acid (14,15-EET 0.128 mg/kg) atone or in combination with LD AUDA on myocardial infarct size as a percentage of the area of risk (IS/AAR) in dogs subjected to 60 min of left anterior descending coronary artery occlusion and 3 h of reperfusion. +p < O.O5 compared with LD AUDA, *p < 0.01 compared with control, **p < 0.00.l compared with control

Figure 3. Changes in 14,15-EET concentrations in the plasma with AUDA treatment

Concentrations of 14,15-epoxyeicosatrienoic acid (14,15-EET) in the coronary venous plasma at 5 and 30 min of reperfusion following treatment with low or high doses of 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA; 0.157 and 0.314 mg/kg, respectively) compared with control values. *p < 0.01 compared with controls