Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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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PMID:Beyond vasodilatation: non-vasomotor roles of epoxyeicosatrienoic acids in the cardiovascular system. 1715 Feb 60

Cyclooxygenase and lipoxygenase metabolism of arachidonic acid produces compounds important in cardiovascular control. Further, arachidonic acid can be metabolised by cytochrome p450 to produce epoxyeicosatrienoic acids (EETs). These derivatives are inactivated by soluble epoxide hydrolase (sEH). The potential role of these EETs in hypertension and cardiac remodelling has been determined using the selective sEH inhibitor, N-adamantyl-N'-dodecylurea (ADU), in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Experiments were performed on male Wistar rats following uninephrectomy alone (UNX rats) or uninephrectomy with administration of DOCA (25 mg every fourth day subcutaneously) and 1% NaCl in drinking water (DOCA-salt rats). ADU (10 mg/kg/d subcutaneously) was administered for 2 wk starting 2 wk after surgery. Cardiovascular structure and function were determined using organ wet weights, histological analysis of collagen and inflammation, isolated heart and thoracic aortic ring preparations, and electrophysiological measurements. DOCA-salt hypertensive rats developed hypertension, hypertrophy, perivascular and interstitial fibrosis, endothelial dysfunction, and prolongation of the cardiac action potential duration within 4 wk. Administration of ADU prevented the further increase in systolic blood pressure and left-ventricular wet weight and normalized endothelial function. ADU treatment did not change inflammatory cell infiltration, collagen deposition, or cardiac action potential duration. EETs may be involved in the development of hypertension and endothelial dysfunction in DOCA-salt rats, but not in excessive collagen deposition or electrophysiological abnormalities.
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PMID:Prevention of hypertension in DOCA-salt rats by an inhibitor of soluble epoxide hydrolase. 1740 62

Since epoxyeicosatrienoic acids (EETs) affect sodium reabsorption in renal tubules and dilate the renal vasculature, we have examined their effects on renal hemodynamics and sodium balance in male rats fed a high-fat (HF) diet by fenofibrate, a peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist and an inducer of cytochrome P-450 (CYP) epoxygenases; by N-methanesulfonyl-6-(2-proparyloxyphenyl)hexanamide (MSPPOH), a selective EET biosynthesis inhibitor; and by 12-(3-adamantane-1-yl-ureido)dodecanoic acid (AUDA), a selective inhibitor of soluble epoxide hydrolase. In rats treated with fenofibrate (30 mg.kg(-1).day(-1) ig) or AUDA (50 mg/l in drinking water) for 2 wk, mean arterial pressure, renal vascular resistance, and glomerular filtration rate were lower but renal blood flow was higher than in vehicle-treated control rats. In addition, fenofibrate and AUDA decreased cumulative sodium balance in the HF rats. Treatment with MSPPOH (20 mg.kg(-1).day(-1) iv) + fenofibrate for 2 wk reversed renal hemodynamics and sodium balance to the levels in control HF rats. Moreover, fenofibrate caused a threefold increase in renal cortical CYP epoxygenase activity, whereas the fenofibrate-induced elevation of this activity was attenuated by MSPPOH. Western blot analysis showed that fenofibrate induced the expression of CYP epoxygenases in renal cortex and microvessels and that the induction effect of fenofibrate was blocked by MSPPOH. These results demonstrate that the fenofibrate-induced increase of CYP epoxygenase expression and the AUDA-induced stabilization of EET production in the kidneys cause renal vascular dilation and reduce sodium retention, contributing to the improvement of abnormal renal hemodynamics and hypertension in HF rats.
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PMID:Increasing or stabilizing renal epoxyeicosatrienoic acid production attenuates abnormal renal function and hypertension in obese rats. 1744 29

Epoxyeicosatrienoic acids (EETs), as metabolites of arachidonic acid, may function as antihypertensive and antiatherosclerotic mediators for vasculature. EETs are degraded by soluble epoxide hydrolase (sEH). Pharmacological inhibition and genetic ablation of sEH have been shown to increase the level of EETs, and treating angiotensin II (Ang II)-infused hypertension rats with sEH-selective inhibitors increased the levels of EETs, with attendant decrease in systolic blood pressure. To elucidate the mechanisms by which Ang II regulates sEH expression, we treated human umbilical vein endothelial cells (ECs) and bovine aortic ECs with Ang II and found increased sEH expression at both the mRNA and protein levels. Transient transfection assays showed that the activity of the human sEH promoter was increased in ECs in response to Ang II. Further analysis of the promoter region of the sEH gene demonstrated that treatment with Ang II, like overexpression of c-Jun/c-Fos, activates the sEH promoter through an AP-1-binding motif. The binding of c-Jun to the AP-1 site of the sEH promoter was confirmed by chromatin immunoprecipitation assays. In contrast, adenovirus overexpression of the dominant-negative mutant of c-Jun significantly attenuated the effects of Ang II on sEH induction. An elevated level of sEH was found in the aortic intima of both spontaneously hypertensive rats and Ang II-infused Wistar rats. Blocking Ang II binding to Ang II receptor 1 by losartan abolished the sEH induction. Thus, AP-1 activation is involved in the transcriptional up-regulation of sEH by Ang II in ECs, which may contribute to Ang II-induced hypertension.
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PMID:Angiotensin II up-regulates soluble epoxide hydrolase in vascular endothelium in vitro and in vivo. 1749 27

Impaired cytochrome P450 epoxygenase enzyme (Cyp2c) regulation contributes to renal damage in angiotensin salt-sensitive hypertension (ANG/HS). We hypothesized that interleukin-6 null mice (IL6-/-) would improve Cyp2c regulation and reduce renal damage in hypertensive mice fed a high salt diet. Systolic blood pressure increased to a greater extent in ANG/HS hypertension as compared to angiotensin (ANG) hypertension but blood pressure did not differ between WT and IL6-/- hypertensive groups. Albuminuria, a marker for renal injury, increased significantly in ANG/HS hypertension in WT mice (5,113 +/- 1,050 mug/day) and was attenuated in the ANG/HS IL6-/- group (1,306 +/- 385 mug/day). Renal Cyp2c protein expression significantly decreased with ANG/HS hypertension in WT mice as compared to high salt alone. However, the ability to upregulate Cyp2c expression in response to a high salt diet was restored in the ANG/HS IL6 deficient hypertensive mice. Renal expression of soluble epoxide hydrolase, which inactivates protective epoxygenase metabolites, was significantly reduced in ANG/HS IL6-/- hypertensive mice compared to the ANG/HS WT group. These data suggest that IL6, while having no effect on blood pressure, impairs regulation of epoxygenase producing Cyp2c, which could contribute to the development of renal injury in angiotensin salt-sensitive hypertension.
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PMID:IL6 suppression provides renal protection independent of blood pressure in a murine model of salt-sensitive hypertension. 1757 66

The P450 eicosanoids epoxyeicosatrienoic acids (EETs) are produced by cytochrome P450 arachidonic acid epoxygenases and metabolized through multiple pathways, including soluble epoxide hydrolase (sEH). Pharmacological inhibition and gene deletion of sEH protect against ischemia/reperfusion injury in brain and heart, and against hypertension-related end-organ damage in kidney. We tested the hypothesis that sEH gene deletion improves survival, recovery of renal function and pathologic ischemic renal damage following transient whole-body ischemia induced by cardiac arrest (CA) and resuscitation. Mice with targeted deletion of sEH (sEH knockout, sEHKO) and C57Bl/6 wild-type control mice were subjected to 10-min CA, followed by cardiopulmonary resuscitation (CPR). Survival in wild-type mice was 93% and 80% at 10 min and 24 h after CA/CPR (n=15). Unexpectedly, survival in sEHKO mice was significantly lower than WT. Only 56% of sEHKO mice survived for 10 min (n=15, p=0.014 compared to WT) and no mice survived for 24 h after CA/CPR (p<0.0001 versus WT). We conclude that sEH plays an important role in cardiovascular regulation, and that reduced sEH levels or function reduces survival from cardiac arrest.
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PMID:Soluble epoxide hydrolase gene deletion reduces survival after cardiac arrest and cardiopulmonary resuscitation. 1772 42

The soluble epoxide hydrolase appears to be a promising target for the development of antihypertensive therapies based on a previously unexplored mechanism of action. Epoxide hydrolases are enzymes that add water to three membered cyclic ethers known as epoxides. The soluble epoxide hydrolase in mammalian systems (sEH) is a member of the alpha/beta-hydrolase fold family of enzymes and it shows a high degree of selectivity for epoxides of fatty acids. The regioisomeric epoxides of arachidonic acid or epoxyeicosanoids (EETs) are particularly good substrates. These EETs appear to be major components of the endothelium-derived hyperpolarizing factors (EDHFs). As such, EETs cause vasodilation and reduce blood pressure. The EETs also are strongly anti-inflammatory and analgesic. By inhibiting sEH, the increase in circulating EETs leads to a reduction in blood pressure in a number of animal models. Potent transition state mimic inhibitors have been developed for the sEH. Some of these sEH inhibitors (sEHIs) show nanomolar to picomolar potency and good pharmacokinetic properties. Because of their unique mode of action they show promise in treating hypertension while reducing problems with end organ failure, vascular inflammation and diabetes. Indeed, the anti-inflammatory properties of the sEHI may make them particularly suitable for treating hypertension in patients with other concomitant metabolic syndromes. They are more potent on a molar basis than most nonsteroidal anti-inflammatory drugs (NSAIDs) in reducing PGE2 in inflammation models, they strongly synergize with NSAIDs, and appear to ameliorate apparently unfavorable eicosanoid profiles associated with some cyclo-oxygenase-2 inhibitors.
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PMID:The soluble epoxide hydrolase as a pharmaceutical target for hypertension. 1787 49

Soluble epoxide hydrolase (sEH) is a therapeutic target for treating hypertension and inflammation. 1,3-Disubstituted ureas functionalized with an ether group are potent sEH inhibitors. However, their relatively low metabolic stability leads to poor pharmacokinetic properties. To improve their bioavailability, we investigated the effect of incorporating various polar groups on the ether function on the inhibition potencies, physical properties, in vitro metabolic stability, and pharmacokinetic properties. The structure-activity relationship studies showed that a hydrophobic linker between the urea group and the ether function is necessary to keep their potency. In addition, urea-ether inhibitors having a polar group such as diethylene glycol or morpholine significantly improved their physical properties and metabolic stability without any loss of inhibitory potency. Furthermore, improved pharmacokinetic properties in murine and canine models were obtained with the resulting inhibitors. These findings will facilitate the usage of sEH inhibitors in animal models of hypertension and inflammation.
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PMID:1,3-disubstituted ureas functionalized with ether groups are potent inhibitors of the soluble epoxide hydrolase with improved pharmacokinetic properties. 1789 81

Soluble epoxide hydrolase (sEH) metabolizes epoxyeicosatrienoic acids and represents a novel therapeutic target in cardiovascular disease treatment. We investigated the relationship among sequence variation in the sEH gene (Ephx2), sEH function, and risk of end-organ injury in strains of spontaneously hypertensive rat (SHRs) differing in their susceptibility to develop brain vascular disease. Brain Ephx2 expression was significantly lower in stroke-prone (SHR/A3) than in stroke-resistant (SHR/N) SHRs (5-fold; P<0.0001). Resequencing of the Ephx2 promoter in the 2 strains identified 3 polymorphisms that significantly influenced promoter transcriptional activity in vitro. Measurements of brain sEH enzyme activity and plasma levels of arachidonate and linoleate metabolites of sEH further suggested significant differences between the 2 strains. Ratios of epoxyoctadecenoic acids to dihydroxyoctadecenoic acids were significantly higher, indicating a lower sEH activity in SHR/A3 than in SHR/N (P<0.0001). Plasma dihydroxyeicosatrienoic acid levels were lower in SHR/A3 than in SHR/N (P<0.0001), but plasma epoxyeicosatrienoic acids levels were similar in the 2 strains. Association analysis of Ephx2 polymorphism in the F2 progeny of an SHR/A3xSHR/N cross showed that animals carrying the SHR/A3 allele of Ephx2 had a greater risk of stroke and associated urinary proteinuria than animals that do not. Investigation of patterns of allelic similarities and differences among multiple stroke-prone and stroke-resistant SHR substrains showed that Ephx2 belongs to a haplotype block shared among all of the stroke-prone but no stroke-resistant substrains. These data support a role for Ephx2 polymorphism on sEH gene expression and function and risk of end-organ injury in the stroke-prone SHR.
Hypertension 2008 Feb
PMID:Altered soluble epoxide hydrolase gene expression and function and vascular disease risk in the stroke-prone spontaneously hypertensive rat. 1808 49

The pioneering work of Gerry Brooks on cyclodiene insecticides led to the discovery of a class of enzymes known as epoxide hydrolases. The results from four decades of work confirm Brooks' first observations that the microsomal epoxide hydrolase is important in foreign compound metabolism. Brooks and associates went on to be the first to carry out a systematic study of the inhibition of this enzyme. A second role for this enzyme family was in the degradation of insect juvenile hormone (JH). JH epoxide hydrolases have now been cloned and expressed from several species, and there is interest in developing inhibitors for them. Interestingly, the distantly related mammalian soluble epoxide hydrolase has emerged as a promising pharmacological target for treating hypertension, inflammatory disease and pain. Tight-binding transition-state inhibitors were developed with good ADME (absorption, distribution, metabolism and excretion). These compounds stabilize endogenous epoxides of fatty acids, including arachidonic acid, which have profound therapeutic effects. Now EHs from microorganisms and plants are used in green chemistry. From his seminal work, Dr Brooks opened the field of epoxide hydrolase research in many directions including xenobiotic metabolism, insect physiology and human health, as well as asymmetric organic synthesis.
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PMID:Gerry Brooks and epoxide hydrolases: four decades to a pharmaceutical. 1838 2


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