Beyond vasodilatation: Non-vasomotor roles of epoxyeicosatrienoic acids in the cardiovascular system

Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Trends in Pharmacological Sciences (Impact Factor: 11.54). 02/2007; 28(1):32-8. DOI: 10.1016/
Source: PubMed


Epoxyeicosatrienoic acids (EETs), derived from arachidonic acid by cytochrome P450 epoxygenases, are potent vasodilators that function as endothelium-derived hyperpolarizing factors in some vascular beds. EETs are rapidly metabolized by soluble epoxide hydrolase to form dihydroxyeicosatrienoic acids (DHETs). Recent reports indicate that EETs have several important non-vasomotor regulatory roles in the cardiovascular system. EETs are potent anti-inflammatory agents and might function as endogenous anti-atherogenic compounds. In addition, EETs and DHETs might stimulate lipid metabolism and regulate insulin sensitivity. Thus, pharmacological inhibition of soluble epoxide hydrolase might be useful not only for hypertension but also for abating atherosclerosis, diabetes mellitus and the metabolic syndrome. Finally, although usually protective in the systemic circulation, EETs might adversely affect the pulmonary circulation.

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    • "Soluble epoxide hydrolase (sEH) is an emerging target for pharmacological treatment of cardiovascular diseases because the inhibition of sEH leads to increased circulating levels of epoxyeicosatrienoic acids (EETs) and other fatty acid epoxides, which mediate endothelium-dependent vasodilation, promote angiogenesis and have anti-inflammatory properties [16-19]. sEH inhibitors (sEHi) were originally developed as antihypertensive and anti-inflammatory agents [20-23]. "
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    ABSTRACT: Background Researches have shown that soluble epoxide hydrolase inhibitors (sEHi) can protect against the development of atherosclerosis. Simultaneously, emerging evidences have implicated the association between fatty acid synthase (FAS) and acute coronary syndrome (ACS). We tested the hypothesis that sEHi could reduce the occurrence of ACS by regulating FAS. Methods Hospitalized ACS patients were selected as the ACS group (n = 65) while healthy normal subjects as the control group (n = 65). The blood levels of lipoproteins, fasting glucose, myocardial enzyme and high-sensitivity C-reactive protein (hs-CRP) were measured within 24 hours after admission. The peripheral blood mononuclear cells (PBMCs) were isolated and cultured. Trans-4-[4-(3-Adamantan-1-ylureido)cyclohexyloxy] benzoic acid (t-AUCB), a kind of sEHi, was then added to cells in various concentrations (0, 10, 50, 100 μmol/L). The expression of FAS, interleukin-6 (IL-6) mRNA and protein was detected by real-time PCR or Western blot, respectively. Results (1) Compared with the control group, the serum concentration of hs-CRP in the ACS group was increased (P<0.05). The expression of FAS, IL-6 mRNA and protein were significantly increased in PBMCs from the ACS group (all P<0.05). Moreover, the levels of FAS and IL-6 mRNA were positively correlated with the serum concentration of hs-CRP (r = 0.685, P<0.01; r = 0.715, P<0.01) respectively. (2) The expression of FAS, IL-6 mRNA and protein in PBMCs from the ACS group were dose-dependently inhibited by sEHi (all P<0.05). Conclusions sEH inhibition regulated FAS and inhibited inflammation in cultured PBMCs from ACS patients, a mechanism that might prevent rupture of atherosclerotic lesions and protect against development of ACS.
    Lipids in Health and Disease 01/2013; 12(1):3. DOI:10.1186/1476-511X-12-3 · 2.22 Impact Factor
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    • "The P450 pathway produces four regioisomeric epoxyeicosatrienoic acids (EETs): 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET. Early studies have revealed diverse physiological functions of EETs, including dilatation of coronary, renal, and cerebral arteries; smooth muscle, endothelial, and epithelial cell proliferation; and anti-inflammatory effects in vascular tissue (Node et al., 1999; Campbell and Falck, 2007; Larsen et al., 2007; Spector and Norris, 2007). EETs function as endothelium-derived hyperpolarizing factors in the coronary circulation and cause vascular smooth muscle relaxation by activating large-conductance, Ca 2ϩ -activated K ϩ channels and membrane hyperpolarization (Campbell et al., 1996; Fisslthaler et al., 1999; Campbell and Falck, 2007). "
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    ABSTRACT: Cytochrome P-450 epoxygenases metabolize arachidonic acid (AA) to epoxyeicosatrienoic acids (EETs). EETs relax vascular smooth muscle by membrane hyperpolarization. 14,15-Epoxyeicosa-5(Z)-enoic acid (14,15-EE5ZE) antagonizes many vascular actions of EETs. EETs are converted to the corresponding dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH). sEH activity in the bovine arterial endothelium and smooth muscle regulates endogenous EETs. This study examined sEH metabolism of 14,15-EE5ZE to 14,15-dihydroxy-eicosa-5(Z)-enoic acid (14,15-DHE5ZE) and the resultant consequences on EET relaxations of bovine coronary arteries (BCAs). BCAs converted 14,15-EE5ZE to 14,15-DHE5ZE. This conversion was blocked by the sEH inhibitor 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA). 14,15-EET relaxations (maximal relaxation, 83.4 ± 4.5%) were inhibited by 14,15-DHE5ZE (10 μM; maximal relaxation, 36.1 ± 9.0%; p < 0.001). In sharp contrast with 14,15-EE5ZE, 14,15-DHE5ZE is a 14,15-EET-selective inhibitor and did not inhibit 5,6-, 8,9-, or 11,12-EET relaxations. 14,15-EET and 11,12-EET relaxations were similar in the presence and absence of AUDA (1 μM). 14,15-EE5ZE inhibited 14,15-EET relaxations to a similar extent with and without AUDA pretreatment. However, 14,15-EE5ZE inhibited 11,12-EET relaxations to a greater extent with than without AUDA pretreatment. These observations indicate that sEH converts 14,15-EE5ZE to 14,15-DHE5ZE, and this alteration influences antagonist selectivity against EET-regioisomers. 14,15-DHE5ZE inhibited endothelium-dependent relaxations to AA but not endothelium-independent relaxations to sodium nitroprusside. A series of sEH-resistant ether analogs of 14,15-EE5ZE was developed, and analogs with agonist and antagonist properties were identified. The present study indicates that conversion of 14,15-EE5ZE to 14,15-DHE5ZE produces a 14,15-EET-selective antagonist that will be a useful pharmacological tool to identify EET receptor(s) and EET function in the cardiovascular system.
    Journal of Pharmacology and Experimental Therapeutics 09/2010; 336(1):47-55. DOI:10.1124/jpet.110.169797 · 3.97 Impact Factor
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    • "Their degradation by sEH generate dihydroxyeicosatrienoic acids, which are less active than their parent epoxides. Decreased sEH activity would therefore be expected to increase intracellular EET levels and prolong their beneficial effects, which include: 1) potent vasodilatation; 2) marked anti-inflammatory action [129]; 3) antioxidant effect by inducing the expression of a set of antioxidant genes, including thioredoxin and superoxide dismutase, as described in GK rat islets [44]; 4) beneficial effects on vessels: EETs inhibit the migration and proliferation of VSMC and, by contrast, stimulate EC proliferation and angiogenesis, particularly in response to hypoxia [127]. Very recent data showed that sEH inhibitors attenuate the progression of renal damage in diabetic GK rats from Taconic and also the development of atherosclerosis in apolipoprotein-E-knockout mice [130], [131]. "
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    ABSTRACT: Inflammation followed by fibrosis is a component of islet dysfunction in both rodent and human type 2 diabetes. Because islet inflammation may originate from endothelial cells, we assessed the expression of selected genes involved in endothelial cell activation in islets from a spontaneous model of type 2 diabetes, the Goto-Kakizaki (GK) rat. We also examined islet endotheliuml/oxidative stress (OS)/inflammation-related gene expression, islet vascularization and fibrosis after treatment with the interleukin-1 (IL-1) receptor antagonist (IL-1Ra). Gene expression was analyzed by quantitative RT-PCR on islets isolated from 10-week-old diabetic GK and control Wistar rats. Furthermore, GK rats were treated s.c twice daily with IL-1Ra (Kineret, Amgen, 100 mg/kg/day) or saline, from 4 weeks of age onwards (onset of diabetes). Four weeks later, islet gene analysis and pancreas immunochemistry were performed. Thirty-two genes were selected encoding molecules involved in endothelial cell activation, particularly fibrinolysis, vascular tone, OS, angiogenesis and also inflammation. All genes except those encoding angiotensinogen and epoxide hydrolase (that were decreased), and 12-lipoxygenase and vascular endothelial growth factor (that showed no change), were significantly up-regulated in GK islets. After IL-1Ra treatment of GK rats in vivo, most selected genes implied in endothelium/OS/immune cells/fibrosis were significantly down-regulated. IL-1Ra also improved islet vascularization, reduced fibrosis and ameliorated glycemia. GK rat islets have increased mRNA expression of markers of early islet endothelial cell activation, possibly triggered by several metabolic factors, and also some defense mechanisms. The beneficial effect of IL-1Ra on most islet endothelial/OS/immune cells/fibrosis parameters analyzed highlights a major endothelial-related role for IL-1 in GK islet alterations. Thus, metabolically-altered islet endothelium might affect the beta-cell microenvironment and contribute to progressive type 2 diabetic beta-cell dysfunction in GK rats. Counteracting islet endothelial cell inflammation might be one way to ameliorate/prevent beta-cell dysfunction in type 2 diabetes.
    PLoS ONE 02/2009; 4(9):e6963. DOI:10.1371/journal.pone.0006963 · 3.23 Impact Factor
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