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)

Inhibition of the soluble epoxide hydrolase (sEH) has beneficial effects on vascular inflammation and hypertension indicating that the enzyme may be a promising target for drug development. As the enzymatic core of the hydrolase domain of the human sEH contains two tyrosine residues (Tyr(383) and Tyr(466)) that are theoretically crucial for enzymatic activity, we addressed the hypothesis that the activity of the sEH may be affected by nitrosative stress. Epoxide hydrolase activity was detected in human and murine endothelial cells as well in HEK293 cells and could be inhibited by either authentic peroxynitrite (ONOO(-)) or the ONOO(-) generator 3-morpholino-sydnonimine (SIN-1). Protection of the enzymatic core with 1-adamantyl-3-cyclohexylurea in vitro decreased sensitivity to SIN-1. Both ONOO(-) and SIN-1 elicited the tyrosine nitration of the sEH protein and mass spectrometry analysis of tryptic fragments revealed nitration on several tyrosine residues including Tyr(383) and Tyr(466). Mutation of the latter residues to phenylalanine was sufficient to abrogate epoxide hydrolase activity. In vivo, streptozotocin-induced diabetes resulted in the tyrosine nitration of the sEH in murine lungs and a significant decrease in its activity. Taken together, these data indicate that the activity of the sEH can be regulated by the tyrosine nitration of the protein. Moreover, nitrosative stress would be expected to potentiate the physiological actions of arachidonic acid epoxides by preventing their metabolism to the corresponding diols.
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PMID:Inhibition of the soluble epoxide hydrolase by tyrosine nitration. 1970 61

Heme oxygenase (HO) and cytochrome P450 (P450)-derived epoxyeicosatrienoic acids (EETs) participate in vascular protection, and recent studies suggest these two systems are functionally linked. We examined the consequences of HO deficiency on P450-derived EETs with regard to body weight, adiposity, insulin resistance, blood pressure, and vascular function in HO-2-null mice. The HO-2-null mice were obese, displayed insulin resistance, and had high blood pressure. HO-2 deficiency was associated with decreases in cyp2c expression, EET levels, HO-1 expression, and HO activity and with an increase in superoxide production and an impairment in the relaxing response to acetylcholine. In addition, HO-2-null mice exhibited increases in serum levels of tumor necrosis factor (TNF)-alpha and macrophage chemoattractant protein (MCP)-1 and a decrease in serum adiponectin levels. Treatment of HO-2-null mice with a dual-activity EET agonist/soluble epoxide hydrolase inhibitor increased renal and vascular EET levels and HO-1 expression, lowered blood pressure, prevented body weight gain, increased insulin sensitivity, reduced subcutaneous and visceral fat, and decreased serum TNF-alpha and MCP-1, while increasing adiponectin and restoring the relaxing responses to acetylcholine. The decrease in cyp2c expression and EETs levels in HO-2-null mice underscores the importance of the HO system in the regulation of epoxygenase levels and suggests that protection against obesity-induced cardiovascular complications requires interplay between these two systems. A deficiency in one of these protective systems may contribute to the adverse manifestations associated with the clinical progression of the metabolic syndrome.
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PMID:Epoxyeicosatrienoic acid agonist rescues the metabolic syndrome phenotype of HO-2-null mice. 1971 90

Soluble epoxide hydrolase (sEH) is a key enzyme involved in the metabolism of epoxy fatty acid mediators such as epoxyeicosatrienoic acids with emerging roles in the regulations of hypertension and inflammation. Inhibitors of human sEH (hsEH) are effective drug candidates for the treatment of cardiovascular diseases. Preparation of hsEH for enzyme inhibition studies has been carried out by using baculovirus expression system. We herein explored the feasibility of expression of hsEH in Escherichia coli cells for the study of high-throughput screening assays of enzyme inhibitors, because the bacterial expression system is easier to handle and more cost-effective than the baculovirus expression system. The functional target enzyme was successfully produced in prokaryotic expression system by an auto-induction method and exhibited comparable enzyme activity to that yielded in baculovirus expression system. The bacterial-hsEH showed similar sensitivity to the baculovirus-hsEH against six reported inhibitors. Overalls indicate that bacterial expression of hsEH employed in the present study is useful for preparing enzymatically active hsEH, leading to effective performance of high-throughput screening assay of hsEH inhibitors and to rapid identification of novel drug candidates for the treatment of cardiovascular diseases.
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PMID:Expression of the human soluble epoxide hydrolase in Escherichia coli by auto-induction for the study of high-throughput inhibition assays. 1978 55

Derived from arachidonic acid, epoxyeicosatrienoic acids function as antihypertensive and antihypertrophic mediators in the cardiovascular system. Epoxyeicosatrienoic acids are generated by soluble epoxide hydrolase, an enzyme hydrolyzing the epoxide moiety of juvenile hormones in insects, and are endothelium-derived hyperpolarizing factors that induce vessel dilation for cardioprotection. Pharmacological inhibition and genetic ablation of soluble epoxide hydrolase increases the level of epoxyeicosatrienoic acids. Recent findings suggest that the level of soluble epoxide hydrolase in the heart and endothelium is upregulated by angiotensin II in vitro in cultured cardiomyocytes and vascular endothelial cells and in vivo in rodent models. Treatment with soluble epoxide hydrolase-selective inhibitors in angiotensin II-infused hypertensive rats increases the level of epoxyeicosatrienoic acids, with attendant decrease in systolic blood pressure. Shear stress, the physiological stimulation of vessel dilation, downregulates soluble epoxide hydrolase and hence increases epoxyeicosatrienoic acid level in endothelial cells. Because of the close association of the angiotensin II/soluble epoxide hydrolase/epoxyeicosatrienoic acid system and blood pressure regulation, pharmacological inhibition of soluble epoxide hydrolase would be a useful approach to prevent and treat angiotensin II-induced cardiac hypertrophy and hypertension, as well as vascular impairments.
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PMID:Linking an insect enzyme to hypertension: angiotensin II-epoxide hydrolase interactions. 1984 58

Recent studies have shown that the renal CYP450 (cytochrome P450) metabolites of AA (arachidonic acid), the vasoconstrictor 20-HETE (20-hydroxyeicosatetraenoic acid) and the vasodilator EETs (epoxyeicosatrienoic acids), play an important role in the pathophysiology of AngII (angiotensin II)-dependent forms of hypertension and the associated target organ damage. The present studies were performed in Ren-2 renin transgenic rats (TGR) to evaluate the effects of chronic selective inhibition of 20-HETE formation or elevation of the level of EETs, alone or in combination, on the course of hypertension and hypertension-associated end-organ damage. Both young (30 days of age) prehypertensive TGR and adult (190 days of age) TGR with established hypertension were examined. Normotensive HanSD (Hannover Sprague-Dawley) rats served as controls. The rats were treated with N-methylsulfonyl-12,12-dibromododec-11-enamide to inhibit 20-HETE formation and/or with N-cyclohexyl-N-dodecyl urea to inhibit soluble epoxide hydrolase and prevent degradation of EETs. Inhibition in TGR of 20-HETE formation combined with enhanced bioavailability of EETs attenuated the development of hypertension, cardiac hypertrophy, proteinuria, glomerular hypertrophy and sclerosis as well as renal tubulointerstitial injury. This was also associated with attenuation of the responsiveness of the systemic and renal vascular beds to AngII without modifying their responses to noradrenaline (norepinephrine). Our findings suggest that altered production and/or action of 20-HETE and EETs plays a permissive role in the development of hypertension and hypertension-associated end-organ damage in this model of AngII-dependent hypertension. This information provides a basis for a search for new therapeutic approaches for the treatment of hypertension.
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PMID:Combined inhibition of 20-hydroxyeicosatetraenoic acid formation and of epoxyeicosatrienoic acids degradation attenuates hypertension and hypertension-induced end-organ damage in Ren-2 transgenic rats. 2005 Aug 26

Cardiovascular diseases (CVDs) remain the leading cause of death in the developed countries. Taking into account the mounting evidence about the role of cytochrome P450 (CYP) enzymes in cardiovascular physiology, CYP polymorphisms can be considered one of the major determinants of individual susceptibility to CVDs. One of the important physiological roles of CYP enzymes is the metabolism of arachidonic acid. CYP epoxygenases such as CYP1A2, CYP2C, and CYP2J2 metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs) which generally possess vasodilating, anti-inflammatory, anti-apoptotic, anti-thrombotic, natriuretic, and cardioprotective effects. Therefore, genetic polymorphisms causing lower activity of these enzymes are generally associated with an increased risk of several CVDs such as hypertension and coronary artery disease. EETs are further metabolized by soluble epoxide hydrolase (sEH) to the less biologically active dihydroxyeicosatrienoic acids (DHETs). Therefore, sEH polymorphism has also been shown to affect arachidonic acid metabolism and to be associated with CVDs. On the other hand, CYP omega-hydroxylases such as CYP4A11 and CYP4F2 metabolize arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE) which has both vasoconstricting and natriuretic effects. Genetic polymorphisms causing lower activity of these enzymes are generally associated with higher risk of hypertension. Nevertheless, some studies have denied the association between polymorphisms in the arachidonic acid pathway and CVDs. Therefore, more research is needed to confirm this association and to better understand the pathophysiologic mechanisms behind it.
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PMID:Effect of cytochrome P450 polymorphism on arachidonic acid metabolism and their impact on cardiovascular diseases. 2009 40

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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PMID:Soluble epoxide hydrolase inhibitors and heart failure. 2043 84

Epoxyeicosatrienoic acids (EETs) are synthesized from arachidonic acid and EETs have a number of beneficial cardiovascular actions. This has led to the concept that EETs and its metabolic pathway can be therapeutically targeted for hypertension and other cardiovascular diseases. One approach has been to prevent the conversion of EETs to their inactive diols by inhibiting the soluble epoxide hydrolase (sEH) enzyme. Inhibition of sEH has been demonstrated to decrease blood pressure in certain experimental models of hypertension, decrease inflammation, and protect organs from damage associated with hypertension and other cardiovascular diseases. The development of sEH inhibitors has reached the point where they are being evaluated in humans. A second therapeutic approach has been to develop EET agonists. EET agonists have been essential for determining the structure function relationship for EETs and determining cell-signaling mechanisms by which EETs exert their cardiovascular actions. More recently, EET agonists have been administered chronically to experimental animal models of hypertension and metabolic syndrome and have been demonstrated to decrease blood pressure, improve insulin signaling, and improve vascular function. These experimental findings provide evidence for sEH inhibitors and EET agonists as a therapeutic approach for cardiovascular diseases, hypertension, and the associated end-organ damage.
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PMID:Targeting epoxides for organ damage in hypertension. 2053 Dec 14

Epoxyeicotrienoic acids (EETs) are cytochrome P450-dependent anti-hypertensive and anti-inflammatory derivatives of arachidonic acid, which are highly abundant in the kidney and considered reno-protective. EETs are degraded by the enzyme soluble epoxide hydrolase (sEH) and sEH inhibitors are considered treatment for chronic renal failure (CRF). We determined whether sEH inhibition attenuates the progression of CRF in the 5/6-nephrectomy model (5/6-Nx) in mice. 5/6-Nx mice were treated with a placebo, an ACE-inhibitor (Ramipril, 40 mg/kg), the sEH-inhibitor cAUCB or the CYP-inhibitor fenbendazole for 8 weeks. 5/6-Nx induced hypertension, albuminuria, glomerulosclerosis and tubulo-interstitial damage and these effects were attenuated by Ramipril. In contrast, cAUCB failed to lower the blood pressure and albuminuria was more severe as compared to placebo. Plasma EET-levels were doubled in 5/6 Nx-mice as compared to sham mice receiving placebo. Renal sEH expression was attenuated in 5/6-Nx mice but cAUCB in these animals still further increased the EET-level. cAUCB also increased 5-HETE and 15-HETE, which derive from peroxidation or lipoxygenases. Similar to cAUCB, CYP450 inhibition increased HETEs and promoted albuminuria. Thus, sEH-inhibition failed to elicit protective effects in the 5/6-Nx model and showed a tendency to aggravate the disease. These effects might be consequence of a shift of arachidonic acid metabolism into the lipoxygenase pathway.
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PMID:Inhibition of the soluble epoxide hydrolase promotes albuminuria in mice with progressive renal disease. 2069 43

The objective of this study was to determine if acute inhibition of 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis or reduced inactivation of epoxyeicosatrienoic acids (EETs) can correct L-N(G)-nitro-arginine-methyl-ester (L-NAME)-induced abnormal vascular reactivity in the perfused mesenteric bed and the carotid artery of spontaneously hypertensive rats (SHR). Administration of L-NAME in drinking water (80 mg/l) to SHR for 3 weeks resulted in abnormal vascular reactivity to norepinephrine and carbachol in the perfused mesenteric vascular bed and carotid artery, and significantly elevated mean arterial blood pressure (244 +/- 9 mm Hg) as compared to SHR controls drinking regular water (176 +/- 3 mm Hg). In the perfused mesenteric vascular bed, the impaired vascular responsiveness to norepinephrine was corrected by acute treatment with N-hydroxy-N'-(4-butyl-2-methylphenyl)formamidine (HET0016), an inhibitor of 20-HETE formation, but not by 1-cyclohexyl-3-dodecyl urea (CDU), an inhibitor of soluble epoxide hydrolase. Treatment with either HET0016 or CDU did not improve impaired carbachol-induced vasodilation in the perfused mesenteric vascular bed. In the isolated carotid artery, treatment with HET0016 corrected the L-NAME-induced increase in norepinephrine-induced vasoconstriction, whereas only CDU treatment could improve impaired carbachol-induced vasodilation. Results of this study indicate that vascular function in a state of compromised nitric oxide formation is differentially modulated by 20-HETE and EETs, and that treatment with HET0016 or CDU may improve vascular function in a state of high blood pressure and endothelial dysfunction.
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PMID:Role of 20-hydroxyeicosatetraenoic and epoxyeicosatrienoic acids in the regulation of vascular function in a model of hypertension and endothelial dysfunction. 2069 31


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