DOCSLIB.ORG

(DHA) Inhibit Angiogenesis, Tumor Growth, and Metastasis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(DHA) Inhibit Angiogenesis, Tumor Growth, and Metastasis Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis Guodong Zhanga,b, Dipak Panigrahyc,d, Lisa M. Mahakiane, Jun Yanga,b, Jun-Yan Liua,b, Kin Sing Stephen Leea,b, Hiromi I. Wetterstenf, Arzu Ulua,b, Xiaowen Hue, Sarah Tame, Sung Hee Hwanga,b, Elizabeth S. Inghame, Mark W. Kieranc,g, Robert H. Weissb,f,h, Katherine W. Ferrarae, and Bruce D. Hammocka,b,1 aDepartment of Entomology, and bComprehensive Cancer Center, University of California, Davis, CA 95616; cVascular Biology Program, Children’s Hospital Boston, and dDepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115; eDepartment of Biomedical Engineering, and fDivision of Nephrology, Department of Internal Medicine, University of California, Davis, CA 95616; gDivision of Pediatric Oncology, Dana- Farber Cancer Institute, Harvard Medical School, Boston, MA 02115; and hUS Department of Veteran’s Affairs Medical Center, Sacramento, CA 95655 Contributed by Bruce D. Hammock, March 8, 2013 (sent for review December 24, 2012) Epidemiological and preclinical evidence supports that omega-3 proangiogenic (25–27) and have been shown to accelerate tumor dietary fatty acids (fish oil) reduce the risks of macular degenera- growth and metastasis by stimulation of tumor angiogenesis (28), tion and cancers, but the mechanisms by which these omega-3 whereas the roles of EDPs in angiogenesis and tumorigenesis lipids inhibit angiogenesis and tumorigenesis are poorly under- have not been studied to date. To this end, we investigated the stood. Here we show that epoxydocosapentaenoic acids (EDPs), actions of EDPs on angiogenesis, tumor growth, and metastasis. which are lipid mediators produced by cytochrome P450 epoxyge- nases from omega-3 fatty acid docosahexaenoic acid, inhibit VEGF- Results and fibroblast growth factor 2-induced angiogenesis in vivo, and EDP Inhibits Angiogenesis in Vivo. To test the actions of EDPs on suppress endothelial cell migration and protease production in angiogenesis, we chemically synthesized all stable EDP regioisom- vitro via a VEGF receptor 2-dependent mechanism. When EDPs ers including 7,8-, 10,11-, 13,14-, 16,17- and 19,20-EDP (4,5-EDP is (0.05 mg·kg−1·d−1) are coadministered with a low-dose soluble chemically unstable) (22) and evaluated their effects on angiogen- epoxide hydrolase inhibitor, EDPs are stabilized in circulation, caus- esis using a Matrigel plug assay in mice (29). Vascular endothelial ing ∼70%inhibitionofprimarytumorgrowthandmetastasis.Con- growth factor (VEGF) is the most important regulator in path- trary to the effects of EDPs, the corresponding metabolites derived ological angiogenesis (30). Implantation of Matrigel plugs con- MEDICAL SCIENCES from omega-6 arachidonic acid, epoxyeicosatrienoic acids, increase taining 100 ng VEGF in mice triggered a robust angiogenic angiogenesis and tumor progression. These results designate response after 4 d of treatment. Addition of 19,20-EDP in the epoxyeicosatrienoic acids and EDPs as unique endogenous media- gel significantly inhibited VEGF-induced angiogenesis in a dose- tors of an angiogenic switch to regulate tumorigenesis and impli- dependent manner, with an EC50 value ∼0.3 μg per gel, illustrating cate a unique mechanistic linkage between omega-3 and omega-6 a potent antiangiogenic effect of 19,20-EDP in vivo (Fig. 1A). We fatty acids and cancers. tested other EDP regioisomers and found all five regioisomers dramatically inhibited VEGF-induced angiogenesis (Fig. 1B). The pidemiological and preclinical evidence supports that a diet 19,20-EDP also significantly inhibited fibroblast growth factor Erich in omega-3 dietary fatty acids is correlated with reduced 2 (FGF-2)–induced angiogenesis (Fig. S1), demonstrating the risks of angiogenic diseases such as macular degeneration (1–4) potential broad-spectrum antiangiogenic effects of EDPs. – and cancers (5 8). However, the mechanisms by which omega-3 fi fatty acids inhibit angiogenesis and cancer are poorly under- EDP Inhibits Angiogenesis in Vitro. Given these in vivo ndings in a stood. A widely accepted theory to explain the health-promoting model system, we next studied whether EDPs have direct anti- effects of omega-3 fatty acids is that they suppress the metabo- angiogenic actions on human endothelial cells. Because 19,20- lism of omega-6 arachidonic acid (ARA) to form proangiogenic EDP is the most abundant EDP regioisomer detected in vivo (16, 19), we focused on this isomer. The 19,20-EDP dramatically in- or proinflammatory eicosanoids or serve as alternative substrates hibited endothelial tube formation after a 6-h treatment in human to generate omega-3 lipid mediators with beneficial actions (9). umbilical vein endothelial cells (HUVECs), ∼63% inhibition at Indeed, the metabolism of omega-3 fatty acids by cyclooxygenase 1 μMand∼91% inhibition at 3 μM, demonstrating its potent (COX) and lipoxygenase (LOX) enzymes generates 3-series pros- antiangiogenic effect in vitro (Fig. 1C). In comparison, DHA had taglandins (10, 11) and leukotrienes (12), as well as unique omega-3 no such effect (Fig. S2 A and B). Because angiogenesis involves autacoids such as resolvins and protectins (13), which have anti- fl multiple cellular steps including endothelial cell migration, pro- in ammatory or antiangiogenic effects. liferation, and production of proteases (31), we studied the step at Besides the intensively studied COX and LOX pathways, which 19,20-EDP inhibited angiogenesis. The 19,20-EDP inhibi- omega-3 and omega-6 fatty acids are also substrates of cyto- ted VEGF-induced HUVEC migration on extracellular matrix chrome P450 (CYP) epoxygenases, which convert them to epoxy (ECM) proteins fibronectin and vitronectin at a similar potency signaling lipids including epoxyeicosatrienoic acids (EETs) de- (∼50% reduction at 1 μM and ∼70% reduction at 3 μM, Fig. 1D rived from omega-6 ARA and epoxydocosapentaenoic acids (EDPs) from omega-3 docosahexaenoic acid (DHA) (14–16). DHA, which is the most abundant omega-3 fatty acid in most Author contributions: G.Z., D.P., M.W.K., K.W.F., and B.D.H. designed research; G.Z., D.P., tissues (17, 18), can efficiently compete with ARA for the me- L.M.M., J.Y., J.-Y.L., K.S.S.L., H.I.W., A.U., X.H., S.T., and E.S.I. performed research; K.S.S.L. tabolism by CYP epoxygenases, leading to replacement of EETs and S.H.H. contributed new reagents/analytic tools; G.Z., D.P., J.Y., J.-Y.L., H.I.W., R.H.W., with EDPs in vivo (16, 19, 20). EETs and EDPs have been in- K.W.F., and B.D.H. analyzed data; and G.Z., D.P., J.Y., J.-Y.L., M.W.K., R.H.W., K.W.F., and B.D.H. wrote the paper. vestigated as autocrine and paracrine mediators to regulate in- fl – Conflict of interest statement: University of California holds patents from the labora- ammation and vascular tone (21 24). In comparison, EDPs have tory of B.D.H. on sEHI for the treatment of inflammation, hypertension, pain and other been reported to have more potency on vasodilation and anti- indications. inflammation than EETs (22, 24). Cumulatively, these results 1To whom correspondence should be addressed. E-mail: [email protected]. imply that EDPs could mediate some of the health-promoting This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. effects of DHA. In terms of angiogenesis and cancer, EETs are 1073/pnas.1304321110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1304321110 PNAS Early Edition | 1of6 Downloaded by guest on October 1, 2021 HO HO HO HO HO A B O O O O O CD31 O 140 VEGF + 140 O 120 Vehicle 100 120 O 100 80 O ** 80 60 O 60 40 # CD31 Hemoglobin VEGF + 40 # # 20 # 10 μg Hemoglobin 20 # (mg protein per g gel) g per protein (mg # 0 19,20-EDP # Ctrl 0.3 3 10 protein per g gel)(mg 0 rl P P P P P t D D D D D 19,20-EDP (mg in gel) C E E E 8- 1-E 4- 7-E 0- 7, ,1 ,1 ,1 ,2 10 13 16 19 Tube formaon C 120 100 80 60 # 40 20 # 0 Branching Points (%) Endothelial cell migraon 120 D 100 80 # 60 # 40 20 0 Ctrl 19,20-EDP (1 μM) 19,20-EDP (3 μM) HUVEC Migration (%) Ctrl 1 3 19,20-EDP (mM) E120 F GVEGF-A P-VEGFR2 140 VEGF-C 100 # 120 80 β-acn 100 19,20- 11,12 DMSO # DMSO 60 80 40 60 ## - EDP EET ## 20 (no 40 MMP-2 Activity (%) MMP-2 Activity 0 VEGF) 20 Ctrl 1 3 0 VEGF (50 ng/mL) 19,20-EDP (mM) Ctrl 1 3 mRNA expression (% to Ctrl) mRNA 19,20-EDP (mM) Fig. 1. EDPs inhibit angiogenesis. (A) The 19,20-EDP inhibited VEGF-induced angiogenesis in a Matrigel plug assay in C57BL/6 mice in a dose-dependent manner (n = 4–6 mice per group). Dose of VEGF is 100 ng per gel. (Left)Quantification of angiogenesis using hemoglobin assay. (Right) Image of representative gels and immunohistochemistry for CD31. (B) All EDP regioisomers inhibited VEGF-induced angiogenesis in mice (n = 6–10 mice per group). Dose of EDP regioisomer was 10 μgpergel.(C) The 19,20-EDP inhibited endothelial tube formation after 6-h treatment in HUVECs. (Left) Calcein AM-stained HUVEC microscopy. (Right) Quantification of tube formation. (D) The 19,20-EDP inhibited VEGF-induced cell migration of HUVECs on extracellular matrix protein fibronectin after 18-h treatment in HUVECs. (Left) Crystal violet-stained HUVEC microscopy. (Right)Quantification of migrated cells. (E) The 19,20-EDP inhibited MMP activity after 4-h treatment in HUVECs. (F)Atadoseof1μM, 19,20-EDP not 14,15-EET, inhibited VEGF-induced VEGFR2 phosphorylation after 10-min treatment in HUVECs.
Load more

Recommended publications
  • Anti-Ulcer Efficacy of Soluble Epoxide Hydrolase Inhibitor TPPU on Diclofenac-Induced Intestinal Ulcers S
    Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2016/03/17/jpet.116.232108.DC1 1521-0103/357/3/529–536$25.00 http://dx.doi.org/10.1124/jpet.116.232108 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 357:529–536, June 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics Anti-Ulcer Efficacy of Soluble Epoxide Hydrolase Inhibitor TPPU on Diclofenac-Induced Intestinal Ulcers s Sumanta Kumar Goswami, Debin Wan, Jun Yang, Carlos A. Trindade da Silva, Christophe Morisseau, Sean D. Kodani, Guang-Yu Yang, Bora Inceoglu, and Bruce D. Hammock Department of Entomology and Nematology, and Comprehensive Cancer Center (S.K.G., D.W., J.Y., C.A.T.S., C.M., S.D.K., B.I., B.D.H.), University of California–Davis, Davis, California; Department of Genetics and Biochemistry (C.A.T.S.), Federal University of Uberlandia, Uberlandia, Minas Gerais, Brazil; Department of Pathology (G.-Y.Y.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois Downloaded from Received January 13, 2016; accepted March 16, 2016 ABSTRACT Proton pump inhibitors such as omeprazole (OME) reduce the with OME (20 mg/kg, PO). In addition, the effect of treatment was severity of gastrointestinal (GI) ulcers induced by nonsteroidal studied on levels of Hb in blood, EETs in plasma, inflammatory jpet.aspetjournals.org anti-inflammatory drugs (NSAIDs) but can also increase the markers such as myeloperoxidase (MPO) in intestinal tissue chance of dysbiosis. The aim of this study was to test the homogenates, and tissue necrosis factor-a (TNF-a) in serum.
    [Show full text]
  • CYP2C19 Variant Mitigates Alzheimer Disease Pathophysiology in Vivo and Postmortem
    ARTICLE OPEN ACCESS CYP2C19 variant mitigates Alzheimer disease pathophysiology in vivo and postmortem Andr´ea L. Benedet, MSc, Lei Yu, PhD, Aur´elie Labbe, PhD, Sulantha Mathotaarachchi, MSc, Correspondence Tharick A. Pascoal, MD, Monica Shin, MSc, Min-Su Kang, BSc, Serge Gauthier, MD, Guy A. Rouleau, MD, PhD, Dr. Rosa-Neto [email protected] Judes Poirier, PhD, David A. Bennett, MD, and Pedro Rosa-Neto, MD, PhD, for the Alzheimer’s Disease Neuroimaging Initiative Neurol Genet 2018;4:e216. doi:10.1212/NXG.0000000000000216 Abstract Objective To verify whether CYP polymorphisms are associated with amyloid-β (Aβ) pathology across the spectrum of clinical Alzheimer disease using in vivo and postmortem data from 2 in- dependent cohorts. Methods A candidate-gene approach tested the association between 5 genes (28 single nucleotide polymorphisms) and Aβ load measured in vivo by the global [18F]florbetapir PET standardized uptake value ratio (SUVR) in 338 Alzheimer’s Disease Neuroimaging Initiative participants. Significant results were then tested using plasma Aβ and CSF Aβ and Aβ/phosphorylated tau (Aβ/p-tau) ratio in the same cohort. The significant association was also generalized to postmortem Aβ load measurement in the Rush Religious Orders Study/Memory and Aging Project cohorts. In addition, global cognition was used as a phenotype in the analysis in both cohorts. Results Analysis of Aβ PET identified a variant in the CYP2C19 gene (rs4388808; p = 0.0006), in which carriers of the minor allele (MA) had a lower global SUVR. A voxel-wise analysis revealed that the variant is associated with a lower Aβ load in the frontal, inferior temporal, and posterior cingulate cortices.
    [Show full text]
  • Epoxyeicosatrienoates Are the Dominant Eicosanoids in Human Lungs Upon Microbial Challenge
    Eur Respir J 2010; 36: 1088–1098 DOI: 10.1183/09031936.00000309 CopyrightßERS 2010 Epoxyeicosatrienoates are the dominant eicosanoids in human lungs upon microbial challenge L. Kiss*, H. Schu¨tte#, W. Padberg", N. Weissmann+, K. Mayer*, T. Gessler*, R. Voswinckel*, W. Seeger* and F. Grimminger* ABSTRACT: Lipoxygenase, cyclo-oxygenase and cytochrome P450 (CYP) products of AFFILIATIONS arachidonic acid (AA) are implicated in pulmonary vasoregulation. The CYP-mediated *University of Gießen Lung Center (UGLC)/Dept of Internal Medicine, epoxyeicosatrienoates (EETs) have been described previously as the predominant eicosanoids "Dept of Surgery, 2+ in human lungs upon stimulation with the Ca ionophore A23187. In this study, we challenged +UGLC/Excellence Cluster perfused human lungs with two microbial agents: Escherichia coli haemolysin (ECH) and formyl- Cardiopulmonary System (ECCPS), methionyl-leucyl-phenylalanine (fMLP). Justus Liebig University, Gießen, and #Dept of Internal Medicine/Infectious Both stimuli elicited pronounced generation of leukotrienes (LTs), hydroxyeicosatetraenoic and Respiratory Diseases, Charite´- acids (HETEs), prostanoids (PTs) and EETs/dihydroxyeicosatrienoic acids (DHETs), as assessed Universita¨tsmedizin Berlin, Berlin, by liquid chromatography–mass spectrometry, paralleled by pulmonary artery pressor response Germany. and lung oedema formation. The maximum buffer concentrations of EETs/DHETs surpassed those CORRESPONDENCE of LTs plus HETEs and PTs by a factor of four (ECH) or three (AA/fMLP). Dual 5-lipoxygenase/
    [Show full text]
  • Ibuprofen Alters Epoxide Hydrolase Activity and Epoxy-Oxylipin Metabolites Associated with Different Metabolic Pathways in Murine Livers
    Ibuprofen alters epoxide hydrolase activity and epoxy-oxylipin metabolites associated with different metabolic pathways in murine livers Shuchita Tiwari University of California, Davis Jun Yang University of California, Davis Christophe Morisseau University of California, Davis Blythe Durbin-Johnson University of California, Davis Bruce Hammock University of California, Davis Aldrin Gomes ( [email protected] ) University of California, Davis Research Article Keywords: sex difference, ibuprofen, liver, microsomal epoxide hydrolase, oxylipin, soluble epoxide hydrolase Posted Date: November 30th, 2020 DOI: https://doi.org/10.21203/rs.3.rs-109297/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Version of Record: A version of this preprint was published at Scientic Reports on March 29th, 2021. See the published version at https://doi.org/10.1038/s41598-021-86284-1. Ibuprofen alters epoxide hydrolase activity and epoxy-oxylipin metabolites associated with different metabolic pathways in murine livers 1 2 2 3 Shuchita Tiwari , Jun Yang , Christophe Morisseau , Blythe Durbin-Johnson , Bruce D. Hammock2 and Aldrin V. Gomes1, 4, * 1Department of Neurobiology, Physiology, and Behavior, University of California, Davis, CA, USA. 2Department of Entomology and Nematology, and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA. 3Department of Public Health Sciences, University of California, Davis, CA, USA. 4Department of Physiology and Membrane Biology,
    [Show full text]
  • A Systematic Review on the Role of Eicosanoid Pathways in Rheumatoid Arthritis
    Advances in Medical Sciences 63 (2018) 22–29 Contents lists available at ScienceDirect Advances in Medical Sciences journal homepage: www.elsevier.com/locate/advms Review article A systematic review on the role of eicosanoid pathways in rheumatoid arthritis a,b, Malvina Hoxha * a Department of Chemical-Toxicological and Pharmacological Evaluation of Drugs, Catholic University Our Lady of Good Counsel, Tirana, Albania b Department of Pharmacological and Biomolecular Sciences, Università degli studi di Milano, Milan, Italy A R T I C L E I N F O A B S T R A C T Article history: Background: Rheumatoid arthritis is characterized by the production of eicosanoids, cytokines, adhesion Received 28 March 2017 molecules, infiltration of T and B lymphocytes in the synovium and oxygen reduction accompanied by the Accepted 18 June 2017 cartilage degradation. Eicosanoids are responsible for the progressive destruction of cartilage and bone, Available online 14 August 2017 however neither steroids, nor the non steroidal anti-inflammatory drugs (NSAIDs), cannot slow down cartilage and bone destruction providing only symptomatic improvement. The current rheumatoid Keywords: arthritis treatment options include mainly the use of disease-modifying anti-rheumatic drugs, the Rheumatoid arthritis corticosteroids, the NSAIDs and biological agents. Inflammation Methods: PubMed, Cochrane, and Embase electronic database were used as the main sources for Arachidonic acid pathway extracting several articles, reviews, original papers in English for further review and analysis on the Prostaglandins Leukotrienes implication of arachidonic acid metabolites with rheumatoid arthritis and different strategies of targeting arachidonic acid metabolites, different enzymes or receptors for improving the treatment of rheumatoid arthritis patients.
    [Show full text]
  • Renal Cytochrome P450 Ω-Hydroxylase and Epoxygenase Activity Are Differentially Modified by Nitric Oxide and Sodium Chloride
    Renal cytochrome P450 ω-hydroxylase and epoxygenase activity are differentially modified by nitric oxide and sodium chloride A.O. Oyekan, … , J. Quilley, J.C. McGiff J Clin Invest. 1999;104(8):1131-1137. https://doi.org/10.1172/JCI6786. Article Renal function is perturbed by inhibition of nitric oxide synthase (NOS). To probe the basis of this effect, we characterized the effects of nitric oxide (NO), a known suppressor of cytochrome P450 (CYP) enzymes, on metabolism of arachidonic acid (AA), the expression of ω-hydroxylase, and the efflux of 20-hydroxyeicosatetraenoic acid (20-HETE) from the isolated kidney. The capacity to convert [14C]AA to HETEs and epoxides (EETs) was greater in cortical microsomes than in medullary microsomes. Sodium nitroprusside (10–100 μM), an NO donor, inhibited renal microsomal conversion of [14C]AA to HETEs and EETs in a dose-dependent manner. 8-bromo cGMP (100 μM), the cell-permeable analogue of cGMP, did not affect conversion of [14C]AA. Inhibition of NOS with Nω-nitro-L-arginine-methyl ester (L-NAME) significantly increased conversion of [14C]AA to HETE and greatly increased the expression of ω-hydroxylase protein, but this treatment had only a modest effect on epoxygenase activity. L-NAME induced a 4-fold increase in renal efflux of 20- HETE, as did L-nitroarginine. Oral treatment with 2% sodium chloride (NaCl) for 7 days increased renal epoxygenase activity, both in the cortex and the medulla. In contrast, cortical ω-hydroxylase activity was reduced by treatment with 2% NaCl. Coadministration of L-NAME and 2% NaCl decreased conversion of [14C]AA to HETEs without affecting epoxygenase activity.
    [Show full text]
  • Integrated Omics-Based Pathway Analyses Uncover CYP
    Apaya et al. Journal of Experimental & Clinical Cancer Research (2019) 38:187 https://doi.org/10.1186/s13046-019-1187-y RESEARCH Open Access Integrated omics-based pathway analyses uncover CYP epoxygenase-associated networks as theranostic targets for metastatic triple negative breast cancer Maria Karmella Apaya1,2,3, Jeng-Yuan Shiau2†, Guo-Shiou Liao4†, Yu-Jen Liang5, Chia-Wei Chen5, Hsin-Chou Yang5, Chi-Hong Chu4, Jyh-Cherng Yu4* and Lie-Fen Shyur1,2,6,7* Abstract Background: Current prognostic tools and targeted therapeutic approaches have limited value for metastatic triple negative breast cancer (TNBC). Building upon current knowledge, we hypothesized that epoxyeicosatrienoic acids (EETs) and related CYP450 epoxygenases may have differential roles in breast cancer signaling, and better understanding of which may uncover potential directions for molecular stratification and personalized therapy for TNBC patients. Methods: We analyzed the oxylipin metabolome of paired tumors and adjacent normal mammary tissues from patients with pathologically confirmed breast cancer (N = 62). We used multivariate statistical analysis to identify important metabolite contributors and to determine the predictive power of tumor tissue metabolite clustering. In vitro functional assays using a panel of breast cancer cell lines were carried out to further confirm the crucial roles of endogenous and exogenous EETs in the metastasis transformation of TNBC cells. Deregulation of associated downstream signaling networks associated with EETs/CYPs was established using transcriptomics datasets from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). Comparative TNBC proteomics using the same tissue specimens subjected to oxylipin metabolomics analysis was used as validation set.
    [Show full text]
  • Microsomal Cytochrome P450 Epoxygenase Induce Hypertension in Rats Fed a High Salt Diet Keiko Makita,* Kihito Takahashi,* Armando Karara,* Harry R
    Experimental and/or Genetically Controlled Alterations of the Renal Microsomal Cytochrome P450 Epoxygenase Induce Hypertension in Rats Fed a High Salt Diet Keiko Makita,* Kihito Takahashi,* Armando Karara,* Harry R. Jacobson,* John R. Falck,§ and Jorge H. Capdevila** Departments of *Medicine and tBiochemistry, Vanderbilt University Medical School, Nashville, Tennessee 37232; and §Department of Molecular Genetics, Southwestern Medical Center, Dallas, Texas 75235 Abstract leukotrienes (1, 2, and references therein). More recently, a considerable body of evidence has demonstrated that micro- Excess dietary salt induces a cytochrome P450 arachidonic somal cytochrome P450 also participates in the bioactivation of acid epoxygenase isoform in rat kidneys (Capdevila, J. H., arachidonic acid (3-5, and references therein). The rat kidney S. Wei, J. Yang, A. Karara, H. R. Jacobson, J. R. Falck, microsomal cytochrome P450 arachidonic acid epoxygenase F. P. Guengerich, and R. N. Dubois. 1992. J. Biol. Chem. catalyzes the NADPH-dependent, enantiospecific, formation of 267:21720-21726). Treatment of rats on a high salt diet 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EET)1 with the epoxygenase inhibitor, clotrimazole, produces sig- (5). To date, epoxygenase activity has been demonstrated in nificant increases in mean arterial blood pressure (122±2 numerous rodent and human tissues, including liver, kidney, and 145±4 mmHg for salt and salt- and clotrimazole-treated brain, pituitary, adrenal, ovaries, lung, and endothelium (3-6). rats, respectively). The salt- and clotrimazole-dependent hy- Interest in defining the functional significance of the cytochrome pertension is accompanied by reductions in the urinary ex- P450 epoxygenase has been stimulated by, among other things, cretion of epoxygenase metabolites and by a selective inhibi- the demonstration of a role for this enzyme in the in vivo tion of the renal microsomal epoxygenase reaction.
    [Show full text]
  • Interaction of Epoxyeicosatrienoic Acids and Adipocyte Fatty Acid-Binding Protein in the Modulation of Cardiomyocyte Contractility
    International Journal of Obesity (2015) 39, 755–761 © 2015 Macmillan Publishers Limited All rights reserved 0307-0565/15 www.nature.com/ijo ORIGINAL ARTICLE Interaction of epoxyeicosatrienoic acids and adipocyte fatty acid-binding protein in the modulation of cardiomyocyte contractility V Lamounier-Zepter1, C Look1, W-H Schunck2, I Schlottmann1, C Woischwill1, SR Bornstein1,AXu3 and I Morano2 BACKGROUND: Adipocyte fatty acid-binding protein (FABP4) is a member of a highly conserved family of cytosolic proteins that bind with high affinity to hydrophobic ligands, such as saturated and unsaturated long-chain fatty acids and eicosanoids. Recent evidence has supported a novel role for FABP4 in linking obesity with metabolic and cardiovascular disorders. In this context, we identified FABP4 as a main bioactive factor released from human adipose tissue that directly suppresses heart contraction in vitro. As FABP4 is known to be a transport protein, it cannot be excluded that lipid ligands are involved in the cardiodepressant effect as well, acting in an additional and/or synergistic way. OBJECTIVE: We investigated a possible involvement of lipid ligands in the negative inotropic effect of adipocyte factors in vitro. RESULTS: We verified that blocking the CYP epoxygenase pathway in adipocytes attenuates the inhibitory effect of adipocyte- conditioned medium (AM) on isolated adult rat cardiomyocytes, thus suggesting the participation of epoxyeicosatrienoic acids (EETs) in the cardiodepressant activity. Analysis of AM for EETs revealed the presence of 5,6-, 8,9-, 11,12- and 14,15-EET, whereas 5,6- EET represented about 45% of the total EET concentration in AM. Incubation of isolated cardiomyocytes with EETs in similar concentrations as found in AM showed that 5,6-EET directly suppresses cardiomyocyte contractility.
    [Show full text]
  • Acti Ons of Epoxygenase M Eta Bolites O N the Preglomerular Vasculature1
    Acti ons of Epoxygenase M eta bolites o n the Preglomerular Vasculature1 John D. lmig,2 L.G. Navar, Richard J. Roman, K. Kishta Reddy, and John P. Falck methacin. In contrast, the vasoconstrictor response to J.D. Imig. L.G. Navar. Department of Physiology. Tu- 5,6-EET was abolished by both removal of the endo- lane University School of Medicine, New Orleans. Lou- thellum or cyclooxygenase inhibition. The thrombox- isiana ane/enderoperoxide receptor inhibitor, SQ 29,548, R.J. Roman. Department of Physiology. Medical Col- resulted in a 60% attenuation of the afferent arteriolar lege of Wisconsin, Milwaukee. Wisconsin vasconstriction to 5,6-EEl. These results indicate that the preglomerular vasoconstriction to 5,6-EEl is cyclo- K.K. Reddy. JR. Falck. Department of Molecular Ge- oxygenase dependent and requires an intact endo- netics University of Texas Southwestern Medical Center Dallas. Texas thelium, whereas the vasodilation to 1 1,12-EET is ste- reoselective and is the result of direct action of the (J. Am. Soc. Nephrol. 1996; 7:23o4-2370) epoxide on the preglomerular vascular smooth mus- cle. ABSTRACT Key Words: Epoxyeicosatrienoic acid. kidney. afferent arte- Epoxygenase metabolites of arachidonic acid are riole. endothellum. cyclooxygenase produced by the kidney and have been implicated in the control of renal blood flow. This study examined A rachidonic acid metabolites of the cytochrome the preglomerular actions of various epoxyeicosatrie- P450 pathway include epoxyeicosatnienoic acids noic acids (EET). By use of the in vitro blood-perfused (EET) and dihydroxyeicosatrienoic acids (DIHETE) juxtamedullary nephron preparation, interlobular formed via epoxygenase enzymes and hydnoxyeicosa- and afferent arteriolar diameter responses to 5,6-EEl, traenoic acids (HETE) formed via P450 w-hydroxybase 8,9-EET, 1 1,12-EEl, and 14,15-EEl were determined.
    [Show full text]
  • Influence of Genetic Variations on Levels of Inflammatory Markers Of
    Int. J. Mol. Sci. 2013, 14, 16402-16413; doi:10.3390/ijms140816402 OPEN ACCESS International Journal of Molecular Sciences ISSN 1422-0067 www.mdpi.com/journal/ijms Brief Report Influence of Genetic Variations on Levels of Inflammatory Markers of Healthy Subjects at Baseline and One Week after Clopidogrel Therapy; Results of a Preliminary Study Payman Shahabi 1, Gérard Siest 1, Bernard Herbeth 1, Daniel Lambert 1, Christine Masson 1, Jean-Sébastien Hulot 2, Sébastien Bertil 3, Pascale Gaussem 3,4,5,† and Sophie Visvikis-Siest 1,†,* 1 UMR INSERM U 1122, IGE-PCV, Faculté de Pharmacie, Université de Lorraine, 30 Rue Lionnois, Nancy 54000, France; E-Mails: [email protected] (P.S.); [email protected] (G.S.); [email protected] (B.H.); [email protected] (D.L.); [email protected] (C.M.) 2 INSERM UMR S956, Université Pierre et Marie Curie, Paris 75005, France; E-Mail: [email protected] 3 AP-HP, Hôpital Européen Georges Pompidou, Paris 75908, France; E-Mails: [email protected] (S.B.); [email protected] (P.G.) 4 Sorbonne Paris Cité, Université Paris Descartes, Paris 75270, France 5 INSERM UMR S765, Faculté de Pharmacie, Université Paris V, Paris 75006, France † These authors contributed equally to this work. * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +33-607-602-569; Fax: +33-383-321-322. Received: 7 June 2013; in revised form: 29 July 2013 / Accepted: 30 July 2013 / Published: 8 August 2013 Abstract: We aimed to assess the association between the most common polymorphisms of cytochrome P450 (CYP) epoxygenases on the plasma levels of inflammatory markers in a population of healthy subjects.
    [Show full text]
  • The Contribution of CYP2C Gene Subfamily Involved in Epoxygenase Pathway of Arachidonic Acids Metabolism to Hypertension Susceptibility in Russian Population
    Clinical and Experimental Hypertension ISSN: 1064-1963 (Print) 1525-6006 (Online) Journal homepage: http://www.tandfonline.com/loi/iceh20 The contribution of CYP2C gene subfamily involved in epoxygenase pathway of arachidonic acids metabolism to hypertension susceptibility in Russian population Alexey Polonikov, Marina Bykanova, Irina Ponomarenko, Svetlana Sirotina, Anna Bocharova, Kseniya Vagaytseva, Vadim Stepanov, Mikhail Churnosov, Olga Bushueva, Maria Solodilova, Yaroslav Shvetsov & Vladimir Ivanov To cite this article: Alexey Polonikov, Marina Bykanova, Irina Ponomarenko, Svetlana Sirotina, Anna Bocharova, Kseniya Vagaytseva, Vadim Stepanov, Mikhail Churnosov, Olga Bushueva, Maria Solodilova, Yaroslav Shvetsov & Vladimir Ivanov (2017): The contribution of CYP2C gene subfamily involved in epoxygenase pathway of arachidonic acids metabolism to hypertension susceptibility in Russian population, Clinical and Experimental Hypertension, DOI: 10.1080/10641963.2016.1246562 To link to this article: http://dx.doi.org/10.1080/10641963.2016.1246562 Published online: 17 May 2017. Submit your article to this journal View related articles View Crossmark data Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iceh20 Download by: [The UC San Diego Library] Date: 17 May 2017, At: 10:09 CLINICAL AND EXPERIMENTAL HYPERTENSION https://doi.org/10.1080/10641963.2016.1246562 The contribution of CYP2C gene subfamily involved in epoxygenase pathway of arachidonic acids metabolism to
    [Show full text]