Article

Soluble Epoxide Hydrolase Inhibitors and Heart Failure

Department of Veterans Affairs, Northern California Health Care System Mather, CA, USA
Cardiovascular Therapeutics (Impact Factor: 2.54). 04/2010; 29(2):99 - 111. DOI: 10.1111/j.1755-5922.2010.00150.x
Source: PubMed

ABSTRACT Cardiovascular disease remains one of the leading causes of death in the Western societies. Heart failure (HF) is due primarily to progressive myocardial dysfunction accompanied by myocardial remodeling. Once HF develops, the condition is, in most cases, irreversible and is associated with a very high mortality rate. Soluble epoxide hydrolase (sEH) is an enzyme that catalyzes the hydrolysis of epoxyeicosatrienoic acids (EETs), which are lipid mediators derived from arachidonic acid through the cytochrome P450 epoxygenase pathway. EETs have been shown to have vasodilatory, antiinflammatory, and cardioprotective effects. When EETs are hydrolyzed by sEH to corresponding dihydroxyeicosatrienoic acids, their cardioprotective activities become less pronounced. In line with the recent genetic study that has identified sEH as a susceptibility gene for HF, the sEH enzyme has received considerable attention as an attractive therapeutic target for cardiovascular diseases. Indeed, sEH inhibition has been demonstrated to have antihypertensive and antiinflammatory actions, presumably due to the increased bioavailability of endogenous EETs and other epoxylipids, and several potent sEH inhibitors have been developed and tested in animal models of cardiovascular disease including hypertension, cardiac hypertrophy, and ischemia/reperfusion injury. sEH inhibitor treatment has been shown to effectively prevent pressure overload- and angiotensin II-induced cardiac hypertrophy and reverse the pre-established cardiac hypertrophy caused by chronic pressure overload. Application of sEH inhibitors in several cardiac ischemia/reperfusion injury models reduced infarct size and prevented the progressive cardiac remodeling. Moreover, the use of sEH inhibitors prevented the development of electrical remodeling and ventricular arrhythmias associated with cardiac hypertrophy and ischemia/reperfusion injury. The data published to date support the notion that sEH inhibitors may represent a promising therapeutic approach for combating detrimental cardiac remodeling and HF.

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    • "c o m / l o c a t e / i j c a r d neovascularization by promoting angiogenesis [13]. Inhibiting sEH can increase the beneficial effects of EETs in animal models of hypertension, atherosclerosis, ischemic heart disease, myocardial hypertrophy, heart failure, diabetes and metabolic syndrome [14] [15] [16] [17] [18] [19] [20]. Therefore, we tested the hypothesis that the sEHi, t-AUCB (trans-4-[4-(3-adamantan-1-yl- ureido)-cyclohexyloxy]-benzoic acid), will improve the angiogenic function of EPCs from AMI patients in order to explore the potential effect of sEHi in treating acute myocardial infarction. "
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    ABSTRACT: BACKGROUND: Epoxyeicosatrienoic acids (EETs) are natural angiogenic mediators regulated by soluble epoxide hydrolase (sEH). Inhibitors of sEH can stabilize EETs levels and were reported to reduce atherosclerosis and inhibit myocardial infarction in animal models. In this work, we investigated whether increasing EETs with the sEH inhibitor t-AUCB would increase angiogenesis related function in endothelial progenitor cells (EPCs) from patients with acute myocardial infarction (AMI). METHODS AND RESULTS: EPCs were isolated from 50 AMI patients and 50 healthy subjects (control). EPCs were treated with different concentrations of t-AUCB for 24h with or without peroxisome proliferator activated receptor γ (PPARγ) inhibitor GW9662. Migration of EPCs was assayed in trans-well chambers. Angiogenesis assays were performed using a Matrigel-Matrix in vitro model. The expression of vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1α (HIF-1α) mRNA and protein in EPCs was measured by real-time PCR or Western blot, respectively. Also, the concentration of EETs in the culture supernatant was detected by ELISA. The activity of EPCs in the AMI patient group was reduced compared to healthy controls. Whereas increasing EET levels with t-AUCB promoted a dose dependent angiogenesis and migration in EPCs from AMI patients. Additionally, the t-AUCB dose dependently increased the expression of the angiogenic factors VEGF and HIF-α. Lastly, we provide evidence that these effects were PPARγ dependent. CONCLUSION: The results demonstrate that the sEH inhibitor positively modulated the functions of EPCs in patients with AMI through the EETs-PPARγ pathway. The present study suggests the potential utility of sEHi in the therapy of ischemic heart disease.
    International journal of cardiology 04/2012; 167(4). DOI:10.1016/j.ijcard.2012.03.167 · 6.18 Impact Factor
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    • "For example, sEH catalyzes the metabolism of anti-inflammatory and vasodilatory epoxyeicosatrienoic acids (EETs) into the more polar and proinflammatory dihydroxyeicosatrieneoic acid (DHETs) (Chacos et al., 1983; Morisseau and Hammock, 2005; Newman et al., 2005). Pharmacological inhibition of sEH by sEH inhibitors (sEHIs) has been demonstrated to be an effective approach to reduce infammation , pain, and hypertension among others (Ingraham et al., 2011; Qiu et al., 2011). Significant progress has been made in recent years in the development of the amide-, urea-and carbamate-based compounds as potent sEHIs (Morisseau et al., 1999). "
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    • "Compounds such as 1,3 disubstituted urea-based old generation CDU (1-cyclohexyl-3-dodecyl-urea), AUDA (12-(3- adamantan-1-yl-ureido)dodecanoic acid), AUDA-BE (butyl ester) and new generation inhibitors like tAUCB with improved oral bioavailability and stability are known to be potent inhibitors of sEH (Jones et al., 2006; Chiamvimonvat et al., 2007; Motoki et al., 2008). Recent studies have confirmed the beneficial effects of sEH inhibitors against IR injury, hypertension and stroke (Chaudhary et al., 2009a; Revermann et al., 2009; Qiu et al., 2010). However, the drawback to these compounds as therapeutic agents includes rapid metabolism, limited oral bioavailability and low water solubility (Jones et al., 2006). "
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    ABSTRACT: Epoxyeicosatrienoic acids (EETs) are cytochrome P450 epoxygenase metabolites of arachidonic acid that are metabolized into dihydroxyepoxyeicosatrienoic acids (DHET) by soluble epoxide hydrolase (sEH). The current investigations were performed to examine the cardioprotective effects of UA-8 (13-(3-propylureido)tridec-8-enoic acid), a synthetic compound that possesses both EET-mimetic and sEH inhibitory properties, against ischaemia-reperfusion injury. Hearts from C57BL/6 mice were perfused in Langendorff mode and subjected to ischaemia reperfusion. Mechanistic studies involved co-perfusing hearts with either 14,15-EEZE (a putative EET receptor antagonist), wortmannin or PI-103 (class-I PI3K inhibitor). H9c2 cells were utilized to investigate the protective effects against mitochondrial injury following anoxia reoxygenation. Perfusion of UA-8 significantly improved postischaemic left ventricular developed pressure (LVDP) and reduced infarction following ischaemia reperfusion compared with control and 11,12-EET. UA-7 (13-(2-(butylamino)-2-oxoacetamido)tridec-8(Z)-enoic acid), a compound lacking sEH inhibitory properties, also improved postischaemic LVDP, while co-perfusion with 14,15-EEZE, wortmannin or PI-103 attenuated the improved recovery. UA-8 prevented anoxia-reoxygenation induced loss of mitochondrial membrane potential and cell death in H9c2 cells, which was blocked by co-treatment of PI-103. UA-8 provides significant cardioprotection against ischaemia reperfusion injury. The effects are attributed to EETs mimetic properties, which limits mitochondrial dysfunction via class-I PI3K signalling.
    British Journal of Pharmacology 10/2010; 162(4):897-907. DOI:10.1111/j.1476-5381.2010.01093.x · 4.99 Impact Factor