Fleming I

References (17)

Title : Role of the soluble epoxide hydrolase in keratinocyte proliferation and sensitivity of skin to inflammatory stimuli - Naeem_2024_Biomed.Pharmacother_171_116127
Author(s) : Naeem Z , Zukunft S , Huard A , Hu J , Hammock BD , Weigert A , Fromel T , Fleming I
Ref : Biomed Pharmacother , 171 :116127 , 2024
Abstract : The lipid content of skin plays a determinant role in its barrier function with a particularly important role attributed to linoleic acid and its derivatives. Here we explored the consequences of interfering with the soluble epoxide hydrolase (sEH) on skin homeostasis. sEH; which converts fatty acid epoxides generated by cytochrome P450 enzymes to their corresponding diols, was largely restricted to the epidermis which was enriched in sEH-generated diols. Global deletion of the sEH increased levels of epoxides, including the linoleic acid-derived epoxide; 12,13-epoxyoctadecenoic acid (12,13-EpOME), and increased basal keratinocyte proliferation. sEH deletion (sEH(-/-) mice) resulted in thicker differentiated spinous and corneocyte layers compared to wild-type mice, a hyperkeratosis phenotype that was reproduced in wild-type mice treated with a sEH inhibitor. sEH deletion made the skin sensitive to inflammation and sEH(-/-) mice developed thicker imiquimod-induced psoriasis plaques than the control group and were more prone to inflammation triggered by mechanical stress with pronounced infiltration and activation of neutrophils as well as vascular leak and increased 12,13-EpOME and leukotriene (LT) B4 levels. Topical treatment of LTB4 antagonist after stripping successfully inhibited inflammation and neutrophil infiltration both in wild type and sEH(-/-) skin. While 12,13-EpoME had no effect on the trans-endothelial migration of neutrophils, like LTB4, it effectively induced neutrophil adhesion and activation. These observations indicate that while the increased accumulation of neutrophils in sEH-deficient skin could be attributed to the increase in LTB4 levels, both 12,13-EpOME and LTB4 contribute to neutrophil activation. Our observations identify a protective role of the sEH in the skin and should be taken into account when designing future clinical trials with sEH inhibitors.
ESTHER : Naeem_2024_Biomed.Pharmacother_171_116127
PubMedSearch : Naeem_2024_Biomed.Pharmacother_171_116127
PubMedID: 38198951

Title : Disruption of Ephx2 in cardiomyocytes but not endothelial cells improves functional recovery after ischemia-reperfusion in isolated mouse hearts - Edin_2023_J.Biol.Chem__103049
Author(s) : Edin M , Gruzdev A , Bradbury JA , Graves J , Lih F , DeGraff L , Fleming I , Zeldin D
Ref : Journal of Biological Chemistry , :103049 , 2023
Abstract : Cytochromes P450 (CYP) metabolize arachidonic acid (AA) to epoxyeicosatrienoic acids (EETs) which have numerous effects. After cardiac ischemia, EET-induced coronary vasodilation increases delivery of oxygen/nutrients to the myocardium, and EET-induced signaling protects cardiomyocytes against post-ischemic mitochondrial damage. Soluble epoxide hydrolase 2 (EPHX2) diminishes the benefits of EETs through hydrolysis to less active dihydroxyeicosatrienoic acids (DHETs). EPHX2 inhibition or genetic disruption improves recovery of cardiac function after ischemia. Immunohistochemical staining revealed EPHX2 expression in cardiomyocytes and some endothelial cells, but little expression in cardiac smooth muscle cells or fibroblasts. To determine specific roles of EPHX2 in cardiac cell types, we generated mice with cell-specific disruption of Ephx2 in endothelial cells (Ephx2(fx/fx)/Tek-cre) or cardiomyocytes (Ephx2(fx/fx)/Myh6-cre) to compare to global Ephx2-deficient mice (global Ephx2(-/-)) and wild-type (Ephx2(fx/fx)) mice in expression, EET hydrolase activity, and heart function studies. Most cardiac EPHX2 expression and activity is in cardiomyocytes with substantially less in endothelial cells. Ephx2(fx/fx)/Tek-cre hearts have similar EPHX2 expression, hydrolase activity, and post-ischemic cardiac function as control Ephx2(fx/fx) hearts. However, Ephx2(fx/fx)/Myh6-cre hearts were similar to global Ephx2(-/-) hearts with significantly diminished EPHX2 expression, decreased hydrolase activity, and enhanced post-ischemic cardiac function compared to Ephx2(fx/fx) hearts. During reperfusion, Ephx2(fx/fx)/Myh6-cre hearts displayed increased ERK activation compared to Ephx2(fx/fx) hearts which could be reversed by EEZE treatment. EPHX2 did not regulate coronary vasodilation in this model. We conclude that EPHX2 is primarily expressed in cardiomyocytes where it regulates EET hydrolysis and post-ischemic cardiac function, whereas endothelial EPHX2 does not play a significant role in these processes.
ESTHER : Edin_2023_J.Biol.Chem__103049
PubMedSearch : Edin_2023_J.Biol.Chem__103049
PubMedID: 36822325

Title : Lipid mediators generated by the cytochrome P450-Epoxide hydrolase pathway - Fromel_2023_Adv.Pharmacol_97_327
Author(s) : Fromel T , Hu J , Fleming I
Ref : Advances in Pharmacology , 97 :327 , 2023
Abstract : The cytochrome P450 (CYP) soluble epoxide hydrolase (sEH) pathway generates a large number of biologically active epoxides and diols from a range of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs). While epoxides of arachidonic acid or epoxyeicosatrienoic acids are probably the best studied of these mediators, epoxides of linoleic acid as well as the fish oils; docosahexaenoic acid and eicosapentaenoic acid have also been attributed signaling actions. Cell and tissue levels of the PUFA epoxides are largely determined by the sEH and in many cases inflammation and chronic diseases, e.g., cardiovascular disease, diabetes and Alzheimer's disease, have been associated with increased sEH expression and the accelerated conversion of PUFA epoxides to their corresponding diols. In low concentrations, the diols act to influence stem and progenitor cells as well as brown adipose tissue but in high concentrations, they tend to have pro-inflammatory and cytotoxic effects that promote disease progression. This review outlines some of the actions to the PUFA epoxides and diols in physiology and pathophysiology as well as the beneficial effects associates with sEH inhibition.
ESTHER : Fromel_2023_Adv.Pharmacol_97_327
PubMedSearch : Fromel_2023_Adv.Pharmacol_97_327
PubMedID: 37236763

Title : Role of the soluble epoxide hydrolase in the hair follicle stem cell homeostasis and hair growth - Naeem_2022_Pflugers.Arch__
Author(s) : Naeem Z , Zukunft S , Gunther S , Liebner S , Weigert A , Hammock BD , Fromel T , Fleming I
Ref : Pflugers Arch , : , 2022
Abstract : Polyunsaturated fatty acids (PUFAs) are used as traditional remedies to treat hair loss, but the mechanisms underlying their beneficial effects are not well understood. Here, we explored the role of PUFA metabolites generated by the cytochrome P450/soluble epoxide hydrolase (sEH) pathway in the regulation of the hair follicle cycle. Histological analysis of the skin from wild-type and sEH(-/-) mice revealed that sEH deletion delayed telogen to anagen transition, and the associated activation of hair follicle stem cells. Interestingly, EdU labeling during the late anagen stage revealed that hair matrix cells from sEH(-/-) mice proliferated at a greater rate which translated into increased hair growth. Similar effects were observed in in vitro studies using hair follicle explants, where a sEH inhibitor was also able to augment whisker growth in follicles from wild-type mice. sEH activity in the dorsal skin was not constant but altered with the cell cycle, having the most prominent effects on levels of the linoleic acid derivatives 12,13-epoxyoctadecenoic acid (12,13-EpOME), and 12,13-dihydroxyoctadecenoic acid (12,13-DiHOME). Fitting with this, the sEH substrate 12,13-EpOME significantly increased hair shaft growth in isolated anagen stage hair follicles, while its diol; 12,13-DiHOME, had no effect. RNA sequencing of isolated hair matrix cells implicated altered Wnt signaling in the changes associated with sEH deletion. Taken together, our data indicate that the activity of the sEH in hair follicle changes during the hair follicle cycle and impacts on two stem cell populations, i.e., hair follicle stem cells and matrix cells to affect telogen to anagen transition and hair growth.
ESTHER : Naeem_2022_Pflugers.Arch__
PubMedSearch : Naeem_2022_Pflugers.Arch__
PubMedID: 35648219

Title : Combined Cardioprotective and Adipocyte Browning Effects Promoted by the Eutomer of Dual sEH\/PPARgamma Modulator - Hartmann_2021_J.Med.Chem_64_2815
Author(s) : Hartmann M , Bibli SI , Tews D , Ni X , Kircher T , Kramer JS , Kilu W , Heering J , Hernandez-Olmos V , Weizel L , Scriba GKE , Krait S , Knapp S , Chaikuad A , Merk D , Fleming I , Fischer-Posovszky P , Proschak E
Ref : Journal of Medicinal Chemistry , 64 :2815 , 2021
Abstract : The metabolic syndrome (MetS) is a constellation of cardiovascular and metabolic symptoms involving insulin resistance, steatohepatitis, obesity, hypertension, and heart disease, and patients suffering from MetS often require polypharmaceutical treatment. PPARgamma agonists are highly effective oral antidiabetics with great potential in MetS, which promote adipocyte browning and insulin sensitization. However, the application of PPARgamma agonists in clinics is restricted by potential cardiovascular adverse events. We have previously demonstrated that the racemic dual sEH/PPARgamma modulator RB394 (3) simultaneously improves all risk factors of MetS in vivo. In this study, we identify and characterize the eutomer of 3. We provide structural rationale for molecular recognition of the eutomer. Furthermore, we could show that the dual sEH/PPARgamma modulator is able to promote adipocyte browning and simultaneously exhibits cardioprotective activity which underlines its exciting potential in treatment of MetS.
ESTHER : Hartmann_2021_J.Med.Chem_64_2815
PubMedSearch : Hartmann_2021_J.Med.Chem_64_2815
PubMedID: 33620196

Title : The Consequences of Soluble Epoxide Hydrolase Deletion on Tumorigenesis and Metastasis in a Mouse Model of Breast Cancer - Kesavan_2021_Int.J.Mol.Sci_22_
Author(s) : Kesavan R , Fromel T , Zukunft S , Brune B , Weigert A , Wittig I , Popp R , Fleming I
Ref : Int J Mol Sci , 22 : , 2021
Abstract : Epoxides and diols of polyunsaturated fatty acids (PUFAs) are bioactive and can influence processes such as tumor cell proliferation and angiogenesis. Studies with inhibitors of the soluble epoxide hydrolase (sEH) in animals overexpressing cytochrome P450 enzymes or following the systemic administration of specific epoxides revealed a markedly increased incidence of tumor metastases. To determine whether PUFA epoxides increased metastases in a model of spontaneous breast cancer, sEH(-/-) mice were crossed onto the polyoma middle T oncogene (PyMT) background. We found that the deletion of the sEH accelerated the growth of primary tumors and increased both the tumor macrophage count and angiogenesis. There were small differences in the epoxide/diol content of tumors, particularly in epoxyoctadecamonoenic acid versus dihydroxyoctadecenoic acid, and marked changes in the expression of proteins linked with cell proliferation and metabolism. However, there was no consequence of sEH inhibition on the formation of metastases in the lymph node or lung. Taken together, our results confirm previous reports of increased tumor growth in animals lacking sEH but fail to substantiate reports of enhanced lymph node or pulmonary metastases.
ESTHER : Kesavan_2021_Int.J.Mol.Sci_22_
PubMedSearch : Kesavan_2021_Int.J.Mol.Sci_22_
PubMedID: 34281173
Gene_locus related to this paper: mouse-hyes

Title : Protective effect of Soluble Epoxide Hydrolase Inhibition in Retinal Vasculopathy associated with Polycystic Kidney Disease - Lin_2020_Theranostics_10_7857
Author(s) : Lin J , Hu J , Schlotterer A , Wang J , Kolibabka M , Awwad K , Dietrich N , Breitschopf K , Wohlfart P , Kannt A , Lorenz K , Feng Y , Popp R , Hoffmann S , Fleming I , Hammes HP
Ref : Theranostics , 10 :7857 , 2020
Abstract : Rationale: Vasoregression secondary to glial activation develops in various retinal diseases, including retinal degeneration and diabetic retinopathy. Photoreceptor degeneration and subsequent retinal vasoregression, characterized by pericyte loss and acellular capillary formation in the absence diabetes, are also seen in transgenic rats expressing the polycystic kidney disease (PKD) gene. Activated Muller glia contributes to retinal vasodegeneration, at least in part via the expression of the soluble epoxide hydrolase (sEH). Given that an increase in sEH expression triggered vascular destabilization in diabetes, and that vasoregression is similar in diabetic mice and PKD rats, the aim of the present study was to determine whether sEH inhibition could prevent retinal vasoregression in the PKD rat. Methods: One-month old male homozygous transgenic PKD rats were randomly allocated to receive vehicle or a sEH inhibitor (sEH-I; Sar5399, 30 mg/kg) for four weeks. Wild-type Sprague-Dawley (SD) littermates received vehicle as controls. Retinal sEH expression and activity were measured by Western blotting and LC-MS, and vasoregression was quantified in retinal digestion preparations. Microglial activation and immune response cytokines were assessed by immunofluorescence and quantitative PCR, respectively. 19,20-dihydroxydocosapentaenoic acid (19,20-DHDP) mediated Notch signaling, microglial activation and migration were assessed in vivo and in vitro. Results: This study demonstrates that sEH expression and activity were increased in PKD retinae, which led to elevated production of 19,20-DHDP and the depression of Notch signaling. The latter changes elicited pericyte loss and the recruitment of CD11b(+)/CD74(+) microglia to the perivascular region. Microglial activation increased the expression of immune-response cytokines, and reduced levels of Notch3 and delta-like ligand 4 (Dll4). Treatment with Sar5399 decreased 19,20-DHDP generation and increased Notch3 expression. Sar5399 also prevented vasoregression by reducing pericyte loss and suppressed microglial activation as well as the expression of immune-response cytokines. Mechanistically, the activation of Notch signaling by Dll4 maintained a quiescent microglial cell phenotype, i.e. reduced both the surface presentation of CD74 and microglial migration. In contrast, in retinal explants, 19,20-DHDP and Notch inhibition both promoted CD74 expression and reversed the Dll4-induced decrease in migration. Conclusions: Our data indicate that 19,20-DHDP-induced alterations in Notch-signaling result in microglia activation and pericyte loss and contribute to retinal vasoregression in polycystic kidney disease. Moreover, sEH inhibition can ameliorate vasoregression through reduced activity of inflammatory microglia. sEH inhibition is thus an attractive new therapeutic approach to prevent retinal vasoregression.
ESTHER : Lin_2020_Theranostics_10_7857
PubMedSearch : Lin_2020_Theranostics_10_7857
PubMedID: 32685025

Title : Soluble epoxide hydrolase promotes astrocyte survival in retinopathy of prematurity - Hu_2019_J.Clin.Invest_129_5204
Author(s) : Hu J , Bibli SI , Wittig J , Zukunft S , Lin J , Hammes HP , Popp R , Fleming I
Ref : J Clinical Investigation , 129 :5204 , 2019
Abstract : Polyunsaturated fatty acids such as docosahexaenoic acid (DHA) positively affect the outcome of retinopathy of prematurity (ROP). Given that DHA metabolism by cytochrome P450 and soluble epoxide hydrolase (sEH) enzymes affects retinal angiogenesis and vascular stability, we investigated the role of sEH in a mouse model of ROP. In WT mice, hyperoxia elicited tyrosine nitration and inhibition of sEH and decreased generation of the DHA-derived diol 19,20-dihydroxydocosapentaenoic acid (19,20-DHDP). Correspondingly, in a murine model of ROP, sEH-/- mice developed a larger central avascular zone and peripheral pathological vascular tuft formation than did their WT littermates. Astrocytes were the cells most affected by sEH deletion, and hyperoxia increased astrocyte apoptosis. In rescue experiments, 19,20-DHDP prevented astrocyte loss by targeting the mitochondrial membrane to prevent the hyperoxia-induced dissociation of presenilin-1 and presenilin-1-associated protein to attenuate poly ADP-ribose polymerase activation and mitochondrial DNA damage. Therapeutic intravitreal administration of 19,20-DHDP not only suppressed astrocyte loss, but also reduced pathological vascular tuft formation in sEH-/- mice. Our data indicate that sEH activity is required for mitochondrial integrity and retinal astrocyte survival in ROP. Moreover, 19,20-DHDP may be more effective than DHA as a nutritional supplement for preventing retinopathy in preterm infants.
ESTHER : Hu_2019_J.Clin.Invest_129_5204
PubMedSearch : Hu_2019_J.Clin.Invest_129_5204
PubMedID: 31479425

Title : The histone demethylase Jarid1b mediates angiotensin II-induced endothelial dysfunction by controlling the 3'UTR of soluble epoxide hydrolase - Vasconez_2019_Acta.Physiol.(Oxf)_225_e13168
Author(s) : Vasconez AE , Janetzko P , Oo JA , Pfluger-Muller B , Ratiu C , Gu L , Helin K , Geisslinger G , Fleming I , Schroder K , Fork C , Brandes RP , Leisegang MS
Ref : Acta Physiol (Oxf) , 225 :e13168 , 2019
Abstract : AIM: The histone demethylase Jarid1b limits gene expression by removing the active methyl mark from histone3 lysine4 at gene promoter regions. A vascular function of Jarid1b is unknown, but a vasoprotective function to inflammatory and hypertrophic stimuli, like angiotensin II (AngII) could be inferred. This hypothesis was tested using Jarid1b knockout mice and the inhibitor PBIT. METHODS: Mice or aortic segments were treated with AngII to induce endothelial dysfunction. Aortae from WT and Jarid1b knockout were studied in organ chambers and endothelium-dependent dilator responses to acetylcholine and endothelium-independent responses to DetaNONOate were recorded after pre-constriction with phenylephrine in the presence or absence of the NO-synthase inhibitor nitro-L-arginine. Molecular mechanisms were investigated with chromatin immunoprecipitation, RNA-Seq, RNA-3'-adaptor-ligation, actinomycin D and RNA-immunoprecipitation. RESULTS: Knockout or inhibition of Jarid1b prevented the development of endothelial dysfunction in response to AngII. This effect was not a consequence of altered nitrite oxide availability but accompanied by a loss of the inflammatory response to AngII. As Jarid1b mainly inhibits gene expression, an indirect effect should account for this observation. AngII induced the soluble epoxide hydrolase (sEH), which degrades anti-inflammatory lipids, and thus promotes inflammation. Knockout or inhibition of Jarid1b prevented the AngII-mediated sEH induction. Mechanistically, Jarid1b maintained the length of the 3'untranslated region of the sEH mRNA, thereby increasing its stability and thus sEH protein expression. Loss of Jarid1b activity therefore resulted in sEH mRNA destabilization. CONCLUSION: Jarid1b contributes to the pro-inflammatory effects of AngII by stabilizing sEH expression. Jarid1b inhibition might be an option for future therapeutics against cardiovascular dysfunction.
ESTHER : Vasconez_2019_Acta.Physiol.(Oxf)_225_e13168
PubMedSearch : Vasconez_2019_Acta.Physiol.(Oxf)_225_e13168
PubMedID: 30076673

Title : Inhibition of soluble epoxide hydrolase prevents diabetic retinopathy - Hu_2017_Nature_552_248
Author(s) : Hu J , Dziumbla S , Lin J , Bibli SI , Zukunft S , de Mos J , Awwad K , Fromel T , Jungmann A , Devraj K , Cheng Z , Wang L , Fauser S , Eberhart CG , Sodhi A , Hammock BD , Liebner S , Muller OJ , Glaubitz C , Hammes HP , Popp R , Fleming I
Ref : Nature , 552 :248 , 2017
Abstract : Diabetic retinopathy is an important cause of blindness in adults, and is characterized by progressive loss of vascular cells and slow dissolution of inter-vascular junctions, which result in vascular leakage and retinal oedema. Later stages of the disease are characterized by inflammatory cell infiltration, tissue destruction and neovascularization. Here we identify soluble epoxide hydrolase (sEH) as a key enzyme that initiates pericyte loss and breakdown of endothelial barrier function by generating the diol 19,20-dihydroxydocosapentaenoic acid, derived from docosahexaenoic acid. The expression of sEH and the accumulation of 19,20-dihydroxydocosapentaenoic acid were increased in diabetic mouse retinas and in the retinas and vitreous humour of patients with diabetes. Mechanistically, the diol targeted the cell membrane to alter the localization of cholesterol-binding proteins, and prevented the association of presenilin 1 with N-cadherin and VE-cadherin, thereby compromising pericyte-endothelial cell interactions and inter-endothelial cell junctions. Treating diabetic mice with a specific sEH inhibitor prevented the pericyte loss and vascular permeability that are characteristic of non-proliferative diabetic retinopathy. Conversely, overexpression of sEH in the retinal Muller glial cells of non-diabetic mice resulted in similar vessel abnormalities to those seen in diabetic mice with retinopathy. Thus, increased expression of sEH is a key determinant in the pathogenesis of diabetic retinopathy, and inhibition of sEH can prevent progression of the disease.
ESTHER : Hu_2017_Nature_552_248
PubMedSearch : Hu_2017_Nature_552_248
PubMedID: 29211719

Title : Cytochrome P450-derived epoxyeicosatrienoic acids accelerate wound epithelialization and neovascularization in the hairless mouse ear wound model - Sander_2011_Langenbecks.Arch.Surg_396_1245
Author(s) : Sander AL , Jakob H , Sommer K , Sadler C , Fleming I , Marzi I , Frank J
Ref : Langenbecks Arch Surg , 396 :1245 , 2011
Abstract : PURPOSE: Epoxyeicosatrienoic acids (EETs) are known to modulate proliferation and angiogenesis in vitro. Tissue levels of EETs are regulated by the cytochrome P450 (CYP) epoxygenases that generate them as well as by the soluble epoxide hydrolase metabolizes them to their less active diols. The aim of this study was to determine the effect of locally administered EETs (11,12- and 14,15-EETs) and the selective sEH inhibitor (sEHI) trans-4-[4-(3-adamantan-1-ylureido)-cyclohexyloxy]-benzoic acid (t-AUCB) on wound healing in vivo.
METHODS: Standardized full thickness dermal wounds were created on the dorsum of hairless mouse ears. Wound epithelialization was directly viewed and measured using intravitalmicroscopy and computerized planimetry every second day until healing was complete. Wound sections were analyzed by immunostaining for endothelial lineage marker CD31, vascular endothelial growth factor (VEGF), and angiogenic cytokine stromal cell-derived factor (SDF) 1alpha on days 2, 4, and 13.
RESULTS: Treatment with EETs and t-AUCB, respectively, significantly accelerated wound epithelialization and neovascularization by synergistic upregulation of SDF1alpha and VEGF in vivo.
CONCLUSIONS: These findings demonstrated that exogenous CYP-derived EETs and globally decreased EET hydrolysis by sEH inhibition significantly accelerated wound epithelialization and neovascularization in unimpaired healing wounds. Given that hypoxia induces CYP expression and subsequently EET-dependent angiogenesis, EETs and sEHIs provide a promising new class of therapeutics for ischemic non-healing wounds.
ESTHER : Sander_2011_Langenbecks.Arch.Surg_396_1245
PubMedSearch : Sander_2011_Langenbecks.Arch.Surg_396_1245
PubMedID: 21887579

Title : Soluble epoxide hydrolase deficiency attenuates neointima formation in the femoral cuff model of hyperlipidemic mice - Revermann_2010_Arterioscler.Thromb.Vasc.Biol_30_909
Author(s) : Revermann M , Schloss M , Barbosa-Sicard E , Mieth A , Liebner S , Morisseau C , Geisslinger G , Schermuly RT , Fleming I , Hammock BD , Brandes RP
Ref : Arterioscler Thromb Vasc Biol , 30 :909 , 2010
Abstract : OBJECTIVE: Epoxyeicosatrienoic acids (EETs) have antiinflammatory effects and are required for normal endothelial function. The soluble epoxide hydrolase (sEH) metabolizes EETs to their less active diols. We hypothesized that knockout and inhibition of sEH prevents neointima formation in hyperlipidemic ApoE(-/-) mice. METHODS AND RESULTS: Inhibition of sEH by 12-(3-adamantan-1-yl-ureido) dodecanoic acid or knockout of the enzyme significantly increased plasma EET levels. sEH activity was detectable in femoral and carotid arteries. sEH knockout or inhibition resulted in a significant reduction of neointima formation in the femoral artery cuff model but not following carotid artery ligation. Although macrophage infiltration occurred abundantly at the site of cuff placement in both sEH(+/+) and sEH(-/-), the expression of proinflammatory genes was significantly reduced in femoral arteries from sEH(-/-) mice. Moreover, an in vivo 5-bromo-2'-deoxyuridine assay revealed that smooth muscle cell proliferation at the site of cuff placement was attenuated in sEH knockout and sEH inhibitor-treated animals. CONCLUSION: These observations suggest that inhibition of sEH prevents vascular remodeling in an inflammatory model but not in a blood flow-dependent model of neointima formation.
ESTHER : Revermann_2010_Arterioscler.Thromb.Vasc.Biol_30_909
PubMedSearch : Revermann_2010_Arterioscler.Thromb.Vasc.Biol_30_909
PubMedID: 20224052

Title : Inhibition of the soluble epoxide hydrolase by tyrosine nitration - Barbosa-Sicard_2009_J.Biol.Chem_284_28156
Author(s) : Barbosa-Sicard E , Fromel T , Keseru B , Brandes RP , Morisseau C , Hammock BD , Braun T , Kruger M , Fleming I
Ref : Journal of Biological Chemistry , 284 :28156 , 2009
Abstract : 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.
ESTHER : Barbosa-Sicard_2009_J.Biol.Chem_284_28156
PubMedSearch : Barbosa-Sicard_2009_J.Biol.Chem_284_28156
PubMedID: 19704161

Title : Epoxyeicosatrienoic acids and the soluble epoxide hydrolase are determinants of pulmonary artery pressure and the acute hypoxic pulmonary vasoconstrictor response - Keseru_2008_FASEB.J_22_4306
Author(s) : Keseru B , Barbosa-Sicard E , Popp R , Fisslthaler B , Dietrich A , Gudermann T , Hammock BD , Falck JR , Weissmann N , Busse R , Fleming I
Ref : FASEB Journal , 22 :4306 , 2008
Abstract : Recent findings have indicated a role for cytochrome P-450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids (EETs) in acute hypoxic pulmonary vasoconstriction (HPV). Given that the intracellular concentration of EETs is determined by the soluble epoxide hydrolase (sEH), we assessed the influence of the sEH and 11,12-EET on pulmonary artery pressure and HPV in the isolated mouse lung. In lungs from wild-type mice, HPV was significantly increased by sEH inhibition, an effect abolished by pretreatment with CYP epoxygenase inhibitors and the EET antagonist 14,15-EEZE. HPV and EET production were greater in lungs from sEH(-/-) mice than from wild-type mice and sEH inhibition had no further effect on HPV, while MSPPOH and 14,15-EEZE decreased the response. 11,12-EET increased pulmonary artery pressure in a concentration-dependent manner and enhanced HPV via a Rho-dependent mechanism. Both 11,12-EET and hypoxia elicited the membrane translocation of a transient receptor potential (TRP) C6-V5 fusion protein, the latter effect was sensitive to 14,15-EEZE. Moreover, while acute hypoxia and 11,12-EET increased pulmonary pressure in lungs from TRPC6(+/-) mice, lungs from TRPC6(-/-) mice did not respond to either stimuli. These data demonstrate that CYP-derived EETs are involved in HPV and that EET-induced pulmonary contraction under normoxic and hypoxic conditions involves a TRPC6-dependent pathway.
ESTHER : Keseru_2008_FASEB.J_22_4306
PubMedSearch : Keseru_2008_FASEB.J_22_4306
PubMedID: 18725458

Title : Soluble epoxide hydrolase is a main effector of angiotensin II-induced hypertension - Jung_2005_Hypertension_45_759
Author(s) : Jung O , Brandes RP , Kim IH , Schweda F , Schmidt R , Hammock BD , Busse R , Fleming I
Ref : Hypertension , 45 :759 , 2005
Abstract : The soluble epoxide hydrolase (sEH) metabolizes vasodilatory epoxyeicosatrienoic acids (EETs) to their di-hydroxy derivatives. We hypothesized that the metabolism of EETs by the sEH contributes to angiotensin II-induced hypertension and tested the effects of a water-soluble sEH inhibitor, 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA) on blood pressure. AUDA (130 microg/mL in drinking water) did not affect blood pressure in normotensive animals but markedly lowered it in mice with angiotensin II-induced hypertension (1 mg/kg per day). The effect of AUDA was accompanied by an increase in urinary salt and water excretion. Intravenous application of AUDA (8 mg/kg) acutely lowered blood pressure and heart rate in animals with angiotensin II-induced hypertension but failed to affect blood pressure in animals with phenylephrine-induced hypertension (29 mg/kg per day). AUDA (0.1 micromol/L) selectively lowered vascular resistance in an isolated perfused kidney preparation from angiotensin II-pretreated mice but not from control mice. In the perfused hind limb and in isolated carotid arteries from angiotensin II-treated mice, AUDA was without effect. The omega-hydroxylase inhibitor N-methylsulfonyl-12,12-dibromododec-11-enamide, which attenuates formation of the potent vasoconstrictor 20-hydroxyeicosatetraenoic acid, decreased tone in carotid arteries from angiotensin II-treated but not from control mice. These data demonstrate that the decrease in blood pressure observed after sEH inhibition in angiotensin II-induced hypertension can be attributed to an initial reduction in heart rate followed by pressure diuresis resulting from increased perfusion of the kidney. Direct vasodilatation of resistance arteries in skeletal muscles does not appear to contribute to the antihypertensive effects of sEH inhibition in mice.
ESTHER : Jung_2005_Hypertension_45_759
PubMedSearch : Jung_2005_Hypertension_45_759
PubMedID: 15699457

Title : The N-terminal domain of mammalian soluble epoxide hydrolase is a phosphatase - Cronin_2003_Proc.Natl.Acad.Sci.U.S.A_100_1552
Author(s) : Cronin A , Mowbray S , Durk H , Homburg S , Fleming I , Fisslthaler B , Oesch F , Arand M
Ref : Proc Natl Acad Sci U S A , 100 :1552 , 2003
Abstract : The mammalian soluble epoxide hydrolase (sEH) is an enzyme with multiple functions, being implicated in detoxification of xenobiotic epoxides as well as in regulation of physiological processes such as blood pressure. The enzyme is a homodimer, in which each subunit is composed of two domains. The 35-kDa C-terminal domain has an alpha/beta hydrolase fold and harbors the catalytic center for the EH activity. The 25-kDa N-terminal domain has a different alpha/beta fold and belongs to the haloacid dehalogenase superfamily of enzymes. The catalytic properties of the enzyme reported so far can all be explained by the action of the C-terminal domain alone. The function of the N-terminal domain, other than in structural stabilization of the dimer, has therefore remained unclear. By structural comparison of this domain to other haloacid dehalogenase family members, we identified a putative active site containing all necessary components for phosphatase activity. Subsequently, we found rat sEH hydrolyzed 4-nitrophenyl phosphate with a rate constant of 0.8 s(-1) and a K(m) of 0.24 mM. Recombinant human sEH lacking the C-terminal domain also displayed phosphatase activity. Presence of a phosphatase substrate did not affect epoxide turnover nor did epoxides affect dephosphorylation by the intact enzyme, indicating both catalytic sites act independently. The enzyme was unable to hydrolyze 4-nitrophenyl sulfate, suggesting its role in xenobiotic metabolism does not extend beyond phosphates. Thus, we propose this domain participates instead in the regulation of the physiological functions associated with sEH.
ESTHER : Cronin_2003_Proc.Natl.Acad.Sci.U.S.A_100_1552
PubMedSearch : Cronin_2003_Proc.Natl.Acad.Sci.U.S.A_100_1552
PubMedID: 12574508

Title : Vascular cytochrome P450 in the regulation of renal function and vascular tone: EDHF, superoxide anions and blood pressure -
Author(s) : Fleming I , Busse R
Ref : Nephrol Dial Transplant , 16 :1309 , 2001
PubMedID: 11427614