Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Cytochrome P450 epoxygenases metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs) which are converted to dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (Ephx2, sEH). To examine the functional role of sEH in the heart, mice with targeted disruption of the Ephx2 gene were studied. Hearts from sEH null mice have undetectable levels of sEH mRNA and protein and cannot convert EETs to DHETs. sEH null mice have normal heart anatomy and basal contractile function, but have higher fatty acid epoxide:diol ratios in plasma and cardiomyocyte cell culture media compared with wild type (WT). sEH null hearts have improved recovery of left ventricular developed pressure (LVDP) and less infarction compared with WT hearts after 20 minutes ischemia. Perfusion with the putative EET receptor antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (10 to 100 nmol/L) before ischemia abolishes this cardioprotective phenotype. Inhibitor studies demonstrate that perfusion with phosphatidylinositol-3 kinase (PI3K) inhibitors wortmannin (200 nmol/L) or LY294002 (5 micromol/L), the ATP-sensitive K+ channel (K(ATP)) inhibitor glibenclamide (1 micromol/L), the mitochondrial K(ATP) (mitoK(ATP)) inhibitor 5-hydroxydecanoate (100 to 200 micromol/L), or the Ca2+-sensitive K+ channel (K(Ca)) inhibitor paxilline (10 micromol/L) abolishes the cardioprotection in sEH null hearts. Consistent with increased activation of the PI3K cascade, sEH null mice exhibit increased cardiac expression of glycogen synthase kinase-3beta (GSK-3beta) phospho-protein after ischemia. Together, these data suggest that targeted disruption of sEH increases the availability of cardioprotective EETs that work by activating PI3K signaling pathways and K+ channels.
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PMID:Role of soluble epoxide hydrolase in postischemic recovery of heart contractile function. 1685 62

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

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 protection from ischemic brain injury enjoyed by females is linked to the female sex hormone 17beta-estradiol. We tested the hypothesis that neuroprotection by estradiol entails the prevention of ischemia-induced inflammatory response, through suppression of the P450 eicosanoids-metabolizing enzyme soluble epoxide hydrolase (sEH). Ovariectomized female rats with and without estradiol replacement underwent 2-hour middle cerebral artery occlusion (MCAO). SEH expression was determined using Western blot, and inflammatory cytokine mRNA levels were measured at 6, 24 and 48 hours after MCAO. Cytokine mRNA was also measured in sEH-knockout mice, and in rats treated with sEH inhibitors. Estradiol reduced basal and post-ischemic sEH expression. MCAO strongly induced mRNA levels of tumor necrosis factor-alpha, interleukin 6, and interleukin 1beta, which was attenuated in sEH-knockouts, but not by sEH inhibitors. Estradiol replacement exhibited a bimodal effect on cytokine mRNA, with increased early and reduced delayed expression. While estradiol suppresses cerebral sEH expression, and sEH suppression diminishes inflammation after MCAO, our findings suggest that the effect of estrogen on inflammation is complex, and only partially explained by sEH suppression.
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PMID:Soluble epoxide hydrolase: regulation by estrogen and role in the inflammatory response to cerebral ischemia. 1798 57

Soluble epoxide hydrolase (sEH) metabolizes epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids. EETs are formed from arachidonic acid during myocardial ischemia and play a protective role against ischemic cell death. Deletion of sEH has been shown to be protective against myocardial ischemia in the isolated heart preparation. We tested the hypothesis that sEH inactivation by targeted gene deletion or pharmacological inhibition reduces infarct size (I) after regional myocardial ischemia-reperfusion injury in vivo. Male C57BL\6J wild-type or sEH knockout mice were subjected to 40 min of left coronary artery (LCA) occlusion and 2 h of reperfusion. Wild-type mice were injected intraperitoneally with 12-(3-adamantan-1-yl-ureido)-dodecanoic acid butyl ester (AUDA-BE), a sEH inhibitor, 30 min before LCA occlusion or during ischemia 10 min before reperfusion. 14,15-EET, the main substrate for sEH, was administered intravenously 15 min before LCA occlusion or during ischemia 5 min before reperfusion. The EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (EEZE) was given intravenously 15 min before reperfusion. Area at risk (AAR) and I were assessed using fluorescent microspheres and triphenyltetrazolium chloride, and I was expressed as I/AAR. I was significantly reduced in animals treated with AUDA-BE or 14,15-EET, independent of the time of administration. The cardioprotective effect of AUDA-BE was abolished by the EET antagonist 14,15-EEZE. Immunohistochemistry revealed abundant sEH protein expression in left ventricular tissue. Strategies to increase 14,15-EET, including sEH inactivation, may represent a novel therapeutic approach for cardioprotection against myocardial ischemia-reperfusion injury.
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PMID:Soluble epoxide hydrolase inhibition and gene deletion are protective against myocardial ischemia-reperfusion injury in vivo. 1883 21

Cytochrome P450 epoxygenases metabolize arachidonic acid (AA) to epoxyeicosatrienoic acids (EETs) which are in turn converted to dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). The main objective of this study was to investigate the protective effects of EETs following ischemic injury using an ex vivo electrocardiogram (EKG) model. Hearts from C57Bl/6, transgenic mice with cardiomyocyte-specific overexpression of CYP2J2 (Tr) and wildtype (WT) littermates were excised and perfused with constant pressure in a Langendorff apparatus. Electrodes were placed superficially at the right atrium and left ventricle to assess EKG waveforms. In ischemic reperfusion experiments hearts were subjected to 20 min of global no-flow ischemia followed by 20 min of reperfusion (R20). The EKG from C57Bl/6 hearts perfused with 1 microM 14,15-EET showed less QT prolongation (QTc) and ST elevation (STE) (QTc=41+/-3, STE=2.3+/-0.3; R20: QTc=42+/-2 ms, STE=1.2+/-0.2mv) than control hearts (QTc=36+/-2, STE=2.3+/-0.2; R20: QTc=53+/-3 ms; STE=3.6+/-0.4mv). Similar results of reduced QT prolongation and ST elevation were observed in EKG recording from CYP2J2 Tr mice (QTc=35+/-1, STE=1.9+/-0.1; R20: QTc=38+/-4 ms, STE=1.3+/-0.2mv) compared to WT hearts. The putative epoxygenase inhibitor MS-PPOH (50 microM) and EET antagonist 14,15-EEZE (10 microM) both abolished the cardioprotective response, implicating EETs in this process. In addition, separate exposure to the K(ATP) channel blockers glibenclamide (1 microM) and HMR1098 (10 microM), or the PKA protein inhibitor H89 (50 nM) during reperfusion abolished the improved repolarization in both the models. Consistent with a role of PKA, CYP2J2 Tr mice had an enhanced activation of the PKAalpha regulatory II subunit in plasma membrane following IR injury. The present data demonstrate that EETs can enhance the recovery of ventricular repolarization following ischemia, potentially by facilitating activation of K(+) channels and PKA-dependent signaling.
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PMID:Epoxyeicosatrienoic acid prevents postischemic electrocardiogram abnormalities in an isolated heart model. 1897 59

Epoxyeicosatrienoic acids (EETs) are polyunsaturated fatty acids synthesized from arachidonic acid by CYP2J2 epoxygenase and inactivated by soluble epoxide hydrolase (sEH or Ephx2) to dihydroxyeicosatrienoic acids. Mitochondrial function following ischemic insult is a critical determinant of reperfusion-induced cell death in the myocardium. The objectives of the current study were to investigate the protective role of EETs in mitochondrial function. Mice with the targeted disruption of the Ephx2 gene, cardiomyocyte-specific overexpression of CYP2J2 or perfused with EETs all have improved postischemic LVDP recovery compared to wild-type (WT). Perfusion with the mPTP opener, atractyloside, abolished the improved postischemic functional recovery observed in CYP2J2 Tr, sEH null and EET perfused hearts. Electron micrographs demonstrated WT hearts to have increased mitochondrial fragmentation and T-tubule swelling compared to CYP2J2 Tr hearts following 20 min global ischemia and 20 min reperfusion. Direct effects of EETs on mitochondria were assessed in isolated rat cardiomyocytes and H9c2 cells. Laser-induced loss of mitochondrial membrane potential (DeltaPsi(m)) and mPTP opening was significantly reduced in cells treated with 14, 15-EET (1 microM). The EET protective effect was blocked by the putative EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (1 muM, 14, 15-EEZE), paxilline (10 microM, BK(Ca) inhibitor) and 5HD (100 microM, K(ATP) inhibitor). Our studies show that EETs can limit mitochondrial dysfunction following cellular stress via a K(+) channel-dependent mechanism.
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PMID:Epoxyeicosatrienoic acids limit damage to mitochondrial function following stress in cardiac cells. 1928 84

Arachidonic acid is metabolized to a number of bioactive eicosanoid molecules by several enzymes, including enzymes of the COX, lipoxygenase and cytochrome P450 (CYP) monooxygenase pathways. Inhibition of the CYP omega-hydroxylase pathway, stimulation of the CYP-epoxygenase pathway and administration of exogenous epoxyeicosatrienoic acids resulted in cardioprotection in animal models of ischemia; contractile function was improved in mouse hearts subjected to global ischemia/reperfusion, and infarct size was reduced in canine and rat hearts. Cardioprotective effects were also achieved when metabolism of the endogenous epoxyeicosatrienoic acids (EETs) by their major enzymatic hydrolysis pathway was blocked in gene knockout mice (EPHX2-/-) or by inhibitors of soluble epoxide hydrolase (sEH), such as 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA). Pretreatment of canine hearts with AUDA dose-dependently reduced infarct size, and AUDA enhanced the infarct-sparing effect of treatment with exogenous EETs. The preliminary results of studies in rodent hearts have also demonstrated that AUDA and AUDA-butyl ester reduce infarct size. These results and others obtained in models of myocardial stunning and hypertrophy suggest that inhibitors of EPHX2 or sEH have therapeutic potential in a broad range of cardiovascular diseases.
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PMID:Soluble epoxide hydrolase: a new target for cardioprotection. 1933 83

Estrogen is a powerful hormone with pleiotropic effects. Estrogens have potent antioxidant effects and are able to reduce inflammation, induce vasorelaxation and alter gene expression in both the vasculature and the heart. Estrogen treatment of cultured cardiac myocytes and endothelial cells rapidly activates NFkappaB, induces heat-shock protein (HSP)-72, a potent intracellular protective protein, and protects cells from simulated ischemia. In in vivo models, estrogens protect against ischemia and trauma/hemorrhage. Estrogens may decrease the expression of soluble epoxide hydrolase, which has deleterious effects on the cardiovascular system through metabolism of epoxyeicosatrienoic acids. Natural (endogenous) estrogens in premenopausal women appear to protect against cardiovascular disease and yet controlled clinical trials have not indicated a benefit from estrogen replacement postmenopause. Much remains to be understood in regards to the many properties of this powerful hormone and how changes in this hormone interact with aging-associated changes. The unexpected negative results of trials of estrogen replacement postmenopause probably arise from our lack of understanding of the many effects of this hormone.
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PMID:Estrogen, aging and the cardiovascular system. 1937 Dec 7


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