Soluble Epoxide Hydrolase Inhibitors and Heart Failure

Department of Veterans Affairs, Northern California Health Care System Mather, CA, USA
Cardiovascular Therapeutics (Impact Factor: 2.36). 04/2010; 29(2):99 - 111. DOI: 10.1111/j.1755-5922.2010.00150.x
Source: PubMed


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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Available from: Jun-Yan Liu, Oct 03, 2015
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    • "Evidence of EET-dependent protection of cardiac function, characterized by protection against cardiac damage, was mainly obtained from studies conducted on postischemic recovery or ischemia/reperfusion models of sEH null hearts (Chaudhary et al. 2009, 2013a,b), or hearts undergoing cardiac hypertrophy (Aboutabl et al. 2011; Althurwi et al. 2013), heart failure (Qiu et al. 2011; Xu et al. 2013), and myocardial infarction (Xu et al. 2013; Shrestha et al. 2014), in response to treatment with sEH inhibitors. To date, fewer studies have reported on the impact of sEH deficiency on physiological function aspects of the coronary circulation. "
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    ABSTRACT: Roles of soluble epoxide hydrolase (sEH), the enzyme responsible for hydrolysis of epoxyeicosatrienoic acids (EETs) to their diols (DHETs), in the coronary circulation and cardiac function remain unknown. We tested the hypothesis that compromising EET hydrolysis/degradation, via sEH deficiency, lowers the coronary resistance to promote cardiac perfusion and function. Hearts were isolated from wild type (WT), sEH knockout (KO) mice and WT mice chronically treated with t-TUCB (sEH inhibitor), and perfused with constant flow at different pre-loads. Compared to WT controls, sEH-deficient hearts required significantly greater basal coronary flow to maintain the perfusion pressure at 100 mmHg and exhibited a greater reduction in vascular resistance during tension-induced heart work, implying a better coronary perfusion during cardiac performance. Cardiac contractility, characterized by developed tension in response to changes in preload, was potentially increased in sEH-KO hearts, manifested by an enlarged magnitude at each step-wise increase in end-diastolic to peak-systolic tension. 14,15-EEZE (EET antagonist) prevented the adaptation of coronary circulation in sEH null hearts whereas responses in WT hearts were sensitive to the inhibition of NO. Cardiac expression of EET synthases (CYP2J2/2C29) was comparable in both genotypic mice whereas, levels of 14,15-, 11,12- and 8,9-EETs were significantly higher in sEH-KO hearts, accompanied with lower levels of DHETs. In conclusion, the elevation of cardiac EETs, as a function of sEH deficiency, plays key roles in the adaptation of coronary flow and cardiac function. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.
    06/2015; 3(6). DOI:10.14814/phy2.12427
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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 · 4.04 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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