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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stroke is the leading cause of severe disability and the third leading cause of death, accounting for one of every 15 deaths in the USA. We investigated the association of polymorphisms in the soluble epoxide hydrolase gene (EPHX2) with incident ischemic stroke in African-Americans and Whites. Twelve single nucleotide polymorphisms (SNPs) spanning EPHX2 were genotyped in a case-cohort sample of 1336 participants from the Atherosclerosis Risk in Communities (ARIC) study. In each racial group, Cox proportional hazard models were constructed to assess the relationship between incident ischemic stroke and EPHX2 polymorphisms. A score test method was used to investigate the association of common haplotypes of the gene with risk of ischemic stroke. In African-Americans, two common EPHX2 haplotypes with significant and opposing relationships to ischemic stroke risk were identified. In Whites, two common haplotypes showed suggestive indication of an association with ischemic stroke risk but, as in African-Americans, these relationships were in opposite direction. These findings suggest that multiple variants exist within or near the EPHX2 gene, with greatly contrasting relationships to ischemic stroke incidence; some associated with a higher incidence and others with a lower incidence.
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PMID:The soluble epoxide hydrolase gene harbors sequence variation associated with susceptibility to and protection from incident ischemic stroke. 1611 16

Soluble epoxide hydrolase (sEH) inhibitors have been demonstrated to have cardiovascular protective actions. This hydrolase enzyme converts fatty acid epoxides to their corresponding diols, and this conversion can alter the biologic activity of these metabolites. We hypothesized that 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA), a sEH inhibitor, would protect stroke-prone spontaneously hypertensive rats from cerebral ischemia. AUDA was administered to 6-week-old male rats for 6 weeks, during which blood pressure was measured by telemetry. Cerebral ischemia was induced by middle cerebral artery occlusion, the size of the cerebral infarct was assessed after 6 hours of ischemia, and the results were expressed as a percentage of the hemisphere infarcted (%HI). Vascular structure and function were assessed using a pressurized arteriograph. Plasma levels of AUDA at the end of the treatment period averaged 5.0 +/- 0.4 ng/mL, and the urinary excretion rate was 99 +/- 21 ng/d. AUDA-treated rats had significantly smaller cerebral infarcts than control rats (36 +/- 4% vs 53 +/- 4% HI, treated versus control, P < 0.05, n = 6). This difference occurred independently of changes in blood pressure. AUDA treatment increased the passive compliance of the cerebral vessels but had no effect on vascular structure. The results of this study provide novel evidence suggesting that the sEH inhibitor AUDA is a possible therapeutic agent for ischemic stroke.
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PMID:An epoxide hydrolase inhibitor, 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA), reduces ischemic cerebral infarct size in stroke-prone spontaneously hypertensive rats. 1630 11

The P450 eicosanoids epoxyeicosatrienoic acids (EETs) are produced in brain and perform important biological functions, including protection from ischemic injury. The beneficial effect of EETs, however, is limited by their metabolism via soluble epoxide hydrolase (sEH). We tested the hypothesis that sEH inhibition is protective against ischemic brain damage in vivo by a mechanism linked to enhanced cerebral blood flow (CBF). We determined expression and distribution of sEH immunoreactivity (IR) in brain, and examined the effect of sEH inhibitor 12-(3-adamantan-1-yl-ureido)-dodecanoic acid butyl ester (AUDA-BE) on CBF and infarct size after experimental stroke in mice. Mice were administered a single intraperitoneal injection of AUDA-BE (10 mg/kg) or vehicle at 30 mins before 2-h middle cerebral artery occlusion (MCAO) or at reperfusion, in the presence and absence of P450 epoxygenase inhibitor N-methylsulfonyl-6-(2-propargyloxyphenyl) hexanamide (MS-PPOH). Immunoreactivity for sEH was detected in vascular and non-vascular brain compartments, with predominant expression in neuronal cell bodies and processes. 12-(3-Adamantan-1-yl-ureido)-dodecanoic acid butyl ester was detected in plasma and brain for up to 24 h after intraperitoneal injection, which was associated with inhibition of sEH activity in brain tissue. Finally, AUDA-BE significantly reduced infarct size at 24 h after MCAO, which was prevented by MS-PPOH. However, regional CBF rates measured by iodoantipyrine (IAP) autoradiography at end ischemia revealed no differences between AUDA-BE- and vehicle-treated mice. The findings suggest that sEH inhibition is protective against ischemic injury by non-vascular mechanisms, and that sEH may serve as a therapeutic target in stroke.
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PMID:Soluble epoxide hydrolase: a novel therapeutic target in stroke. 1744 Apr 91

Single nucleotide polymorphisms (SNPs) in the human EPHX2 gene have recently been implicated in susceptibility to cardiovascular disease, including stroke. EPHX2 encodes for soluble epoxide hydrolase (sEH), an important enzyme in the metabolic breakdown of arachidonic acid-derived eicosanoids referred to as epoxyeicosatrienoic acids (EETs). We previously demonstrated that EETs are protective against ischemic cell death in culture. Therefore, we tested the hypothesis that polymorphisms in the human EPHX2 gene alter sEH enzyme activity and affect neuronal survival after ischemic injury in vitro. Human EPHX2 mutants were recreated by site-directed mutagenesis and fused downstream of TAT protein transduction domain. Western blot analysis and immunocytochemistry staining revealed high-transduction efficiency of human TAT-sEH variants in rat primary cultured cortical neurons, associated with increased metabolism of 14,15-EET to corresponding 14,15-dihydroxyeicosatrienoic acid. A human variant of sEH with Arg103Cys amino acid substitution, previously demonstrated to increase sEH enzymatic activity, was associated with increased cell death induced in cortical neurons by oxygen-glucose deprivation (OGD) and reoxygenation. In contrast, the Arg287Gln mutation was associated with reduced sEH activity and protection from OGD-induced neuronal cell death. We conclude that sequence variations in the human EPHX2 gene alter susceptibility to ischemic injury and neuronal survival in a manner linked to changes in the hydrolase activity of the enzyme. The findings suggest that human EPHX2 mutations may in part explain the genetic variability in sensitivity to ischemic brain injury and stroke outcome.
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PMID:Polymorphisms in the human soluble epoxide hydrolase gene EPHX2 linked to neuronal survival after ischemic injury. 1746 77

The P450 eicosanoids epoxyeicosatrienoic acids (EETs) are endogenous lipid mediators produced in the brain by P450 epoxygenases and metabolized through multiple pathways, including soluble epoxide hydrolase (sEH). Epoxyeicosatrienoic acids play important functions in the brain, including regulation of cerebral blood flow and protection from ischaemic brain injury. We previously demonstrated that ischaemic preconditioning induces cytochrome P450 2C11 epoxygenase (CYP2C11) expression in the brain, and that pharmacological inhibition and genetic deletion of sEH increases EETs and protects against stroke-induced brain damage. However, the expression profiles of CYP2C11 and sEH in normal brain remain unknown. In agreement with previous reports in peripheral vessels, we here demonstrate by immunofluorescence double-labelling that within cerebral parenchymal microvessels, sEH-immunoreactivity (IR) is localized to the vascular smooth muscle layer. Unexpectedly, however, analysis of large cerebral conduit arteries such as the middle cerebral artery revealed CYP2C11 and sEH expression in extrinsic perivascular nerves. Double-labelling studies revealed that CYP2C11- and sEH-IR predominantly colocalized with neuronal nitric oxide synthase-IR within perivascular nerve fibres. Significant colocalization for CYP2C11 and sEH was also observed with the parasympathetic markers vasoactive intestinal peptide and choline actetyltransferase, in addition to the sensory fibre markers calcitonin gene-related peptide and substance P. No colocalization was observed for either CYP2C11 or sEH with the sympathetic nerve markers dopamine beta-hydroxylase or neuropeptide Y. The presence of enzymes involved in production and inactivation of EETs within extrinsic parasympathetic and sensory vasodilator fibres suggests a novel role for EETs in the neurogenic control of cerebral arteries.
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PMID:A novel role for P450 eicosanoids in the neurogenic control of cerebral blood flow in the rat. 1763 71

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.
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PMID:Altered soluble epoxide hydrolase gene expression and function and vascular disease risk in the stroke-prone spontaneously hypertensive rat. 1808 49

Epoxyeicosatrienoic acids (EETs) are cytochrome P450 metabolites of arachidonic acid, which function in the brain to regulate cerebral blood flow and protect against ischemic brain injury. EETs are converted by soluble epoxide hydrolase (sEH) to the corresponding inactive diol metabolites. Previous animal studies have indicated that sEH gene deletion or treatment with sEH inhibitors results in increased levels of EETs and protection against stroke-induced brain damage. To begin elucidating the underlying mechanism for these effects, we sought to determine the distribution, expression, and activity of sEH in human brain samples obtained from patients with no neurological changes/pathologies. Immunohistochemical analyses showed the distribution of sEH mainly in the neuronal cell bodies, oligodendrocytes, and scattered astrocytes. Surprisingly, in the choroid plexus, sEH was found to be highly expressed in ependymal cells. Vascular localization of sEH was evident in several regions, where it was highly expressed in the smooth muscles of the arterioles. Western blot analysis and enzyme assays confirmed the presence of sEH in the normal brain. Our results indicate differential localization of sEH in the human brain, thus suggestive of an essential role for this enzyme in the central nervous system. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.
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PMID:Distribution and expression of soluble epoxide hydrolase in human brain. 1831 71

In stroke-prone spontaneously hypertensive rats (SHRSP) end-organ damage is markedly accelerated by high-salt (HS) intake. Since epoxyeicosatrienoic acids (EETs) possess vasodepressor and natriuretic activities, we examined whether a soluble epoxide hydrolase (sEH) inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), to inhibit the metabolism of EETs, would protect against pathologic changes in SHRSP. Seven-week-old male SHRSP were treated as follows: normal salt (NS), NS + AUDA, HS and HS + AUDA. Systolic blood pressure (SBP) (205 +/- 4 v 187 +/- 7 mmHg) and proteinuria (3.7 +/- 0.2 v 2.6 +/- 0.2 mg/6 h), but not plasma EETs (11.0 +/- 0.9 v 9.7 +/- 1.1 ng/ml), were significantly increased at 9 weeks of age in HS v NS SHRSP. HS was associated with fibrinoid degeneration and hypertrophy of arterioles in the kidney and perivascular fibrosis and contraction band necrosis in the heart. AUDA ameliorated these early salt-dependent changes in saline-drinking SHRSP and increased plasma levels of EETs but did not affect water and electrolyte excretion. sEH inhibition may provide a therapeutic strategy for treating salt-sensitive hypertension and its sequelae.
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PMID:Soluble epoxide hydrolase inhibitor, AUDA, prevents early salt-sensitive hypertension. 1850 49

Epoxyeicosatrienoic acids (EETs) are potent vasodilators produced from arachidonic acid by cytochrome P-450 (CYP) epoxygenases and metabolized to vicinal diols by soluble epoxide hydrolase (sEH). In the brain, EETs are produced by astrocytes and the vascular endothelium and are involved in the control of cerebral blood flow (CBF). Recent evidence, however, suggests that epoxygenases and sEH are present in perivascular vasodilator nerve fibers innervating the cerebral surface vasculature. In the present study, we tested the hypothesis that EETs are nerve-derived relaxing factors in the cerebral circulation. We first traced these fibers by retrograde labeling in the rat to trigeminal ganglia (TG) and sphenopalatine ganglia (SPG). We then examined the expression of CYP epoxygenases and sEH in these ganglia. RT-PCR and Western blot analysis identified CYP2J3 and CYP2J4 epoxygenase isoforms and sEH in both TG and SPG, and immunofluorescence double labeling identified CYP2J and sEH immunoreactivity in neuronal cell bodies of both ganglia. To evaluate the functional role of EETs in neurogenic vasodilation, we elicited cortical hyperemia by electrically stimulating efferent cerebral perivascular nerve fibers and by chemically stimulating oral trigeminal fibers with capsaicin. Cortical blood flow responses were monitored by laser-Doppler flowmetry. Local administration to the cortical surface of the putative EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (30 mumol/l) attenuated CBF responses to electrical and chemical stimulation. These results suggest that EETs are produced by perivascular nerves and play a role in neurogenic vasodilation of the cerebral vasculature. The findings have important implications to such clinical conditions as migraine, vasospasm after subarachnoid hemorrhage, and stroke.
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PMID:Epoxyeicosanoids as mediators of neurogenic vasodilation in cerebral vessels. 1930 46

Inhibition of soluble epoxide hydrolase (SEH), the enzyme responsible for degradation of vasoactive epoxides, protects against cerebral ischemia in rats. However, the molecular and biological mechanisms that confer protection in normotension and hypertension remain unclear. Here we show that 6 weeks of SEH inhibition via 2 mg/day of 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA) in spontaneously hypertensive stroke-prone (SHRSP) rats protects against cerebral ischemia induced by middle cerebral artery occlusion, reducing percent hemispheric infarct and neurodeficit score without decreasing blood pressure. This level of cerebral protection was similar to that of the angiotensin-converting enzyme inhibitor, enalapril, which significantly lowered blood pressure. SEH inhibition is also protective in normotensive Wistar-Kyoto (WKY) rats, reducing both hemispheric infarct and neurodeficit score. In SHRSP rats, SEH inhibition reduced wall-to-lumen ratio and collagen deposition and increased cerebral microvessel density, although AUDA did not alter middle cerebral artery structure or microvessel density in WKY rats. An apoptosis mRNA expression microarray of brain tissues from AUDA-treated rats revealed that AUDA modulates gene expression of mediators involved in the regulation of apoptosis in neural tissues of both WKY and SHRSP rats. Hence, we conclude that chronic SEH inhibition protects against cerebral ischemia via vascular protection in SHRSP rats and neural protection in both the SHRSP and WKY rats, indicating that SEH inhibition has broad pharmacological potential for treating ischemic stroke.
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PMID:Soluble epoxide inhibition is protective against cerebral ischemia via vascular and neural protection. 1943 85


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