Soluble Epoxide Hydrolase in Atherosclerosis

Authors: YiXin Jim Wang Arzu Ulu LeNing Zhang Bruce Hammock

Publish Date: 2010/04/13

Volume: 12, Issue: 3, Pages: 174-183

PDF Link

Abstract

Like many eicosanoids epoxyeicosatrienoic acids EETs have multiple biological functions including reduction of blood pressure inflammation and atherosclerosis in multiple species Hydration of EETs by the soluble epoxide hydrolase sEH is the major route of their degradation to the less bioactive diols Inhibition of the sEH stabilizes EETs thus enhancing the beneficial effects of EETs Human data show an association of sEH Ephx2 gene polymorphisms with increased risk of atherosclerosis and cardiovascular diseases These data suggest a potential therapeutic effect of sEH inhibitors sEHI in the treatment of atherosclerosis Indeed two laboratories reported independently that using different sEHIs in apolipoprotein E–deficient mice significantly attenuated atherosclerosis development and aneurysm formation The antiatherosclerotic effects of sEHI are correlated with elevation in EET levels and associated with reduction of lowdensity lipoprotein and elevation of highdensity lipoprotein cholesterols as well as attenuation of expression of proinflammatory genes and proteins In addition the antihypertensive effects and improvement of endothelial function also contribute to the mechanism of the antiatherosclerotic effects of sEHI The broad spectrum of biological action of EETs and sEHIs with multiple biological beneficial actions provides a promising new class of therapeutics for atherosclerosis and other cardiovascular diseasesAtherosclerosis is a chronic vascular inflammatory disease characterized by chronic inflammation and abnormalities in cholesterol transport leading to foam cell and plaque formation in the arterial wall It is a major cause of cardiac death with several lifethreatening cardiovascular complications including myocardial infarction and stroke when the atherosclerotic plaque ruptures Currently the major pharmacologic intervention for atherosclerosis is to use statins alone or in combination with niacin and fibrates to lower lowdensity lipoprotein LDL and to increase highdensity lipoprotein HDL in addition to modifications in diet Statins inhibit 3hydroxy3methylglutaryl coenzyme A HMGCoA reductase the ratelimiting enzyme in cholesterol synthesis and increase LDL cholesterol clearance Statins have been shown to be effective in reducing cholesterol and attenuation of atherosclerosis and cardiovascular risk in patients Moreover a newgeneration statin namely rosuvastatin has been shown to attenuate coronary atherosclerosis 1 In this clinical trial known as A Study to Evaluate the Effect of Rosuvastatin on Intravascular UltrasoundDerived Coronary Atheroma Burden ASTEROID highintensity rosuvastatin therapy not only dramatically decreased LDL cholesterol but also attenuated atherosclerotic plaques in the coronary arteries 1 Antiinflammatory drugs such as lowdose aspirin and antihypertensive drugs in particular angiotensinconverting enzyme inhibitors and angiotensin receptor blockers also have beneficial effects in the prevention of atherosclerosis and reducing the cardiovascular risk when used prophylactically or in combination with statinsSeveral key enzymes and receptors in the arachidonic acid AA cascade are important targets for atherosclerosis 2 A novel target is the soluble epoxide hydrolase sEH A major function of the sEH is to metabolize the epoxides of AA and linoleic acid that are the regioisomers of epoxyeicosatrienoic acids EETs and epoxyoctadecenoic acids EpOMEs to their corresponding diols dihydroxyeicosatrienoic acid DHET and dihydroxyoctadecenoic acid DiHOME respectively The epoxides of AA EETs have protective effects on the vasculature kidney and the heart Inhibitors of sEH reduce inflammation and prevent the development of atherosclerotic plaques presumably via an increase in EETs and other epoxy lipids as well as a decrease in the corresponding diols 3•• 4••The purpose of this review is to discuss the role of EETs and sEH in the pathogenesis of atherosclerosis as well as the preclinical and clinical evidence that supports the rationale to use sEHI as therapeutics for prevention and treatment of atherosclerosis and its complicationsThe arachidonic acid AA cascade AA is metabolized by three major oxidative pathways 1 cyclooxygenase COX forming prostaglandins and related eicosanoids 2 lipoxygenase LOX forming leukotrienes and related compounds and 3 CYP450 forming epoxides 2C/2J and 20HETEs 4A/4F Epoxyeicosatrienoic acids EETs are vasodilatory and antiinflammatory whereas 20HETE antagonizes these effects of EETs Soluble epoxide hydrolase sEH degrades EETs to their less bioactive corresponding dihydroxyeicosatrienoic acid DHETs thereby reducing beneficial effects of EETs Inhibitors of sEH stabilize EETs and prolong the duration of action of EETs thus enhancing the effects of reducing hypertension inflammation and painThese biochemically shortlived EETs are quickly degraded by sEH into their corresponding diols or DHETs which generally are less bioactive The sEH thus reduces the beneficial effects of EETs 9 Epoxide hydration is the dominant pathway of EETs degradation but EETs are also metabolized by β oxidation chain elongation hydroxylation incorporation into the cell membrane phospholipids and/or even via other enzymes in the arachidonate cascade 10 Early sEH inhibitors were competitive substrates or substrates that were slowly turned over These compounds were of limited use in vivo The first transition state mimic inhibitors potent enough for in vivo use were based on urea carbamate and amide pharmacophores 9 11 Inhibitors of sEH can enhance these effects by stabilizing EETs and other lipid epoxides and by reducing some proinflammatory diols 12 Thus inhibition of sEH has been proposed as a therapeutic target to treat hypertension and its complications 13 Indeed a variety of sEH inhibitors have been shown to decrease blood pressure in a number of rodent models of hypertension 7 14 15 In addition to vasorelaxation EETs have also been shown to be antiinflammatory analgesic and mildly angiogenic 7 10 The efficacy of sEH inhibitors has been demonstrated in animal models to reduce cardiac hypertrophy 16 attenuate sepsisinduced inflammation 12 and decrease inflammatory pain 17 The biological effects seen in these studies can be attributed to inhibition of sEH activity evidenced by an increase in plasma EET to DHET ratio Furthermore sEH is widely expressed in the liver kidney heart brain and other tissues thus the antiinflammatory effects of sEHI offer novel treatment options in a range of disease models including atherosclerosis pain stroke and diabetes 3•• 4•• 17 18 19 20sEHIs have been shown to reverse cardiac hypertrophy in several animal models In a mouse model of angiotensin II Ang IIinduced cardiac hypertrophy treatment with a potent sEHI 11methanesulfonylpiperidin4yl34trifluoromethoxyphenylurea TUPS significantly reduced cardiac hypertrophy and improved cardiac contractility 21 The in vitro experiment in neonatal cardiac myocytes treated with Ang II revealed that the antihypertrophic effect of sEHI is concentration dependent and associates with downregulation of COX2 via an increase in the ratio of EET to DHET indicating that antihypertrophic efficacy of sEHI acts directly on cardiomyocytes independent of blood pressure regulation 22 In a murine model of cardiac hypertrophy induced by thoracic aortic banding TAC the sEHI blocked nuclear factor–κB NFκB activation thereby reducing inflammation and decreased the gene expression of the cardiac hypertrophy markers including atrial natriuretic factor skeletal actin and major histocompatibility complex MHC compared with that in vehicle control group 22 Later on more insight in the role of sEH in cardiac hypertrophy came with another study in two different rat models spontaneously hypertensive rats SHRs and Ang IIinfused Wistar rats 16 This study revealed that Ang II dosedependently upregulated cardiac sEH expression involving AP1 transcription factor activation which could be reversed by losartan an angiotensin type 1 AT1 receptor antagonist In a murine model of coronary artery ligation sEHIs are also found to be protective against heart failure and cardiac arrhythmias after myocardial infarct by reducing infarct size and preventing cardiac remodeling 23 In this study at 3 weeks after ligation the ratios of EET to DHET and EpOME to DiHOME were increased along with a decrease in cytokines in the sEHItreated compared with the sEHIuntreated group Because the sEHI had cardioprotective effects in variety animal models of cardiac hypertrophy and heart failure including non–Ang IIinduced models multiple mechanisms may be involved in the mode of actionsEH is expressed in many organisms including plants nematodes and humans It was reported in the 1970s that laboratory rats have by far the lowest levels of hepatic sEH among the mammals studied Increased sEH gene expression and activity along with renal eicosanoid metabolism have been reported to participate in the pathogenesis of hypertension in SHRs 14 It has been observed in many laboratories that increased sEH is associated with a lowering of blood pressure in several but not all strains of SHR 24 25 Investigating the role of sEH in hypertensive animals Fornage et al 26 reported that substrains of SHR and its wildtype control WKY rats obtained from different sources eg Heidelberg vs Charles River show differences in the level of Ephx2 sEH gene expression activity and protein abundance In order to understand the underlying mechanisms of differences in sEH in these rat strains the authors hypothesized that single nucleotide polymorphisms SNPs may be responsible for the differences in sEH as well as blood pressure in these animals The genotyping of the renal cortical preparations from SHR and WKY revealed four SNPs which create two Ephx2 alleles These variants included G405A G560A C780T and G1465A NCBI NM 022936 reference sequence The SHR Heidelberg sequence was found to be identical to that of SpragueDawley rats

Keywords: