Restricted accessReview articleFirst published online 2015-05
Whatever Happened to the Epoxyeicosatrienoic Acid-Like Endothelium-Derived Hyperpolarizing Factor? The Identification of Novel Classes of Lipid Mediators and Their Role in Vascular Homeostasis
Significance: Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid (AA) to generate epoxyeicosatrienoic acids (EETs). The latter are biologically active and reported to act as an endothelium-derived hyperpolarizing factor as well as to affect angiogenic and inflammatory signaling pathways. Recent Advances: In addition to AA, the CYP enzymes also metabolize the ω-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid and docosahexaenoic acid to generate bioactive lipid epoxide mediators. The latter can be more potent than the EETs, but their actions are under investigated. The ω3-epoxides, like the EETs, are metabolized by the soluble epoxide hydrolase (sEH) to corresponding diols, and epoxide hydrolase inhibition increases epoxide levels and demonstrates anti-hypertensive as well as anti-inflammatory effects. Critical Issues: It seems that the overall consequences of CYP activation largely depend on enzyme substrate preference and the endogenous ω-3/ω-6 PUFA ratio. Future Directions: More studies combining PUFA profiling with cell signaling and disease studies are required to determine the spectrum of molecular pathways affected by the different ω-6 and ω-3 PUFA epoxides and diols. Such information may help improve dietary studies aimed at promoting health via ω-3 PUFA supplementation and/or sEH inhibition. Antioxid. Redox Signal. 22, 1273–1292.
Get full access to this article
View all access options for this article.
References
1.
AgborLN, WalshMT, BobergJR, and WalkerMK. Elevated blood pressure in cytochrome P4501A1 knockout mice is associated with reduced vasodilation to omega-3 polyunsaturated fatty acids. Toxicol Appl Pharmacol, 264: 351–360, 2012.
2.
AiD, FuY, GuoD, TanakaH, WangN, TangC, HammockBD, ShyyJYJ, and ZhuY. Angiotensin II up-regulates soluble epoxide hydrolase in vascular endothelium in vitro and in vivo. Proc Natl Acad Sci U S A, 104: 9018–9023, 2007.
3.
AlvarezJ, MonteroM, and García-SanchoJ. Cytochrome P450 may link intracellular Ca2+ stores with plasma membrane Ca2+ influx. Biochem J, 274: 193–197, 1991.
4.
ArnoldC, MarkovicM, BlosseyK, WallukatG, FischerR, DechendR, KonkelA, vonSC, LuftFC, MullerDN, RotheM, and SchunckWH. Arachidonic acid-metabolizing cytochrome P450 enzymes are targets of ω-3 fatty acids. J Biol Chem, 285: 32723–32733, 2010.
5.
ArterburnLM, HallEB, and OkenH. Distribution, interconversion, and dose response of n-3 fatty acids in humans. Am J Clin Nutr, 83: 1467S–1476S, 2006.
6.
AstaritaG, McKenzieJH, WangB, StrassburgK, DoneanuA, JohnsonJ, BakerA, HankemeierT, MurphyJ, VreekenRJ, LangridgeJ, and KangJX. A protective lipidomic biosignature associated with a balanced omega-6/omega-3 ratio in fat-1 transgenic mice. PLoS One, 9: e96221, 2014.
7.
This reference has been deleted.
8.
AugoodC, ChakravarthyU, YoungI, VioqueJ, de JongPT, BenthamG, RahuM, SelandJ, SoubraneG, TomazzoliL, TopouzisF, VingerlingJR, and FletcherAE. Oily fish consumption, dietary docosahexaenoic acid and eicosapentaenoic acid intakes, and associations with neovascular age-related macular degeneration. Am J Clin Nutr, 88: 398–406, 2008.
9.
BaggaD, WangL, Farias-EisnerR, GlaspyJA, and ReddyST. Differential effects of prostaglandin derived from omega-6 and omega-3 polyunsaturated fatty acids on COX-2 expression and IL-6 secretion. Proc Natl Acad Sci U S A, 100: 1751–1756, 2003.
10.
Barbosa-SicardE, FrömelT, KeserüB, BrandesRP, MorisseauC, HammockBD, BraunT, KrügerM, and FlemingI. Inhibition of the soluble epoxide hydrolase by tyrosine nitration. J Biol Chem, 284: 28156–28163, 2009.
11.
Barbosa-SicardE, MarkovicM, HoneckH, ChristB, MullerDN, and SchunckWH. Eicosapentaenoic acid metabolism by cytochrome P450 enzymes of the CYP2C subfamily. Biochem Biophys Res Commun, 329: 1275–1281, 2005.
12.
BellienJ, IacobM, GutierrezL, IsabelleM, LaharyA, ThuillezC, and JoannidesR. Crucial role of NO and endothelium-derived hyperpolarizing factor in human sustained conduit artery flow-mediated dilatation. Hypertension, 48: 1088–1094, 2006.
13.
BellienJ, JoannidesR, IacobM, ArnaudP, and ThuillezC. Evidence for a basal release of a cytochrome-related endothelium-derived hyperpolarizing factor in the radial artery in humans. Am J Physiol Heart Circ Physiol, 290: H1347–H1352, 2006.
14.
BlasbalgTL, HibbelnJR, RamsdenCE, MajchrzakSF, and RawlingsRR. Changes in consumption of omega-3 and omega-6 fatty acids in the United States during the 20th century. Am J Clin Nutr, 93: 950–962, 2011.
15.
BoettcherM and de WitC. Distinct endothelium-derived hyperpolarizing factors emerge in vitro and in vivo and are mediated in part via connexin 40-dependent myoendothelial coupling. Hypertension, 57: 802–808, 2011.
16.
BolzSS, FisslthalerB, PieperhoffS, de WitC, FlemingI, BusseR, and PohlU. Antisense oligonucleotides against cytochrome P450 2C8 attenuate EDHF-mediated Ca2+ changes and dilation in isolated resistance arteries. FASEB J, 14: 255–260, 2000.
17.
BuiP, SolaimaniP, WuX, and HankinsonO. 2,3,7,8-Tetrachlorodibenzo-p-dioxin treatment alters eicosanoid levels in several organs of the mouse in an aryl hydrocarbon receptor-dependent fashion. Toxicol Appl Pharmacol, 259: 143–151, 2012.
18.
BurnsKD, CapdevilaJ, WeiS, BreyerMD, HommaT, and HarrisRC. Role of cytochrome P-450 epoxygenase metabolites in EGF signaling in renal proximal tubule. Am J Physiol, 269: C831–C840, 1995.
19.
BurnsRN and MoniriNH. Agonism with the omega-3 fatty acids alpha-linolenic acid and docosahexaenoic acid mediates phosphorylation of both the short and long isoforms of the human GPR120 receptor. Biochem Biophys Res Commun, 396: 1030–1035, 2010.
20.
BusseR, EdwardsG, FeletouM, FlemingI, VanhouttePM, and WestonAH. EDHF: bringing the concepts together. Trends Pharmacol Sci, 23: 374–380, 2002.
21.
BystromJ, WrayJA, SugdenMC, HolnessMJ, SwalesKE, WarnerTD, EdinML, ZeldinDC, GilroyDW, and Bishop-BaileyD. Endogenous epoxygenases are modulators of monocyte/macrophage activity. PLoS One, 6: e26591, 2011.
22.
CalvielloG, SuHM, WeylandtKH, FasanoE, SeriniS, and CittadiniA. Experimental evidence of omega-3 polyunsaturated fatty acid modulation of inflammatory cytokines and bioactive lipid mediators: their potential role in inflammatory, neurodegenerative, and neoplastic diseases. Biomed Res Int, 2013: 743171, 2013.
23.
CampbellWB, GebremedhinD, PrattPF, and HarderDR. Identification of epoxyeicosatrienoic acids as endothelium-derived hyperpolarizing factors. Circ Res, 78: 415–423, 1996.
24.
CapdevilaJH, KishoreV, DishmanE, BlairIA, and FalckJR. A novel pool of rat liver inositol and ethanolamine phospholipids contains epoxyeicosatrienoic acids (EETs). Biochem Biophys Res Commun, 146: 638–644, 1987.
25.
CarolinaBJ, EduardoS, LuizFMP, AugustoS, FrancielleB, FernandaTDR, SimoneH, FranciscoABD, JuanJL, MarcioNC, and NelsonJLD. Linoleic and α-linolenic fatty acid consumption over three generations exert cumulative regulation of hepatic expression of genes related to lipid metabolism. Genes Nutr, 9: 405, 2014.
26.
ChangCL, TorrejonC, JungUJ, GrafK, and DeckelbaumRJ. Incremental replacement of saturated fats by n-3 fatty acids in high-fat, high-cholesterol diets reduces elevated plasma lipid levels and arterial lipoprotein lipase, macrophages and atherosclerosis in LDLR−/−mice. Atherosclerosis, 234: 401–409, 2014.
27.
ChenJK, FalckJR, ReddyKM, CapdevilaJ, and HarrisRC. Epoxyeicosatrienoic acids and their sulfonimide derivatives stimulate tyrosine phosphorylation and induce mitogenesis in renal epithelial cells. J Biol Chem, 273: 29254–29261, 1998.
28.
ChenJK, WangD-W, FalckJR, CapdevilaJ, and HarrisRC. Transfection of an active cytochrome P450 arachidonic acid epoxygenase indicates that 14,15-epoxyeicosatrienoic acid functions as an intracellular messenger in response to epidermal growth factor. J Biol Chem, 274: 4764–4769, 1999.
29.
ChenJ-K, CapdevilaJ, and HarrisRC. Heparin-binding EGF-like growth factor mediates the biological effects of P450 arachidonate epoxygenase metabolites in epithelial cells. Proc Natl Acad Sci U S A, 99: 6029–6034, 2002.
30.
ChenL, AckermanR, and GuoAM. 20-HETE in neovascularization. Prostaglandins Other Lipid Mediat, 98: 63–68, 2012.
31.
CheranovSY, KarpurapuM, WangD, ZhangB, VenemaRC, and RaoGN. An essential role for SRC-activated STAT-3 in 14,15-EET-induced VEGF expression and angiogenesis. Blood, 111: 5581–5591, 2008.
32.
ChiangN, FredmanG, BackhedF, OhSF, VickeryT, SchmidtBA, and SerhanCN. Infection regulates pro-resolving mediators that lower antibiotic requirements. Nature, 484: 524–528, 2012.
CuiPH, PetrovicN, and MurrayM. The omega-3 epoxide of eicosapentaenoic acid inhibits endothelial cell proliferation by p38 MAP kinase activation and cyclin D1/CDK4 down-regulation. Br J Pharmacol, 162: 1143–1155, 2011.
35.
DingY, FrömelT, PoppR, FalckJR, SchunckWH, and FlemingI. The biological actions of 11,12-epoxyeicosatrienoic acid in endothelial cells are specific to the R/S-enantiomer and require the Gs protein. J Pharmacol Exp Ther, 350: 14–21, 2014.
36.
DouliasPT, GreeneJL, GrecoTM, TenopoulouM, SeeholzerSH, DunbrackRL, and IschiropoulosH. Structural profiling of endogenous S-nitrosocysteine residues reveals unique features that accommodate diverse mechanisms for protein S-nitrosylation. Proc Natl Acad Sci U S A, 107: 16958–16963, 2010.
37.
DunworthWP, Cardona-CostaJ, BozkulakEC, KimJD, MeadowsS, FischerJC, WangY, CleaverO, QyangY, OberEA, and JinSW. Bone morphogenetic protein 2 signaling negatively modulates lymphatic development in vertebrate embryos. Circ Res, 114: 56–66, 2014.
38.
EgertS and StehleP. Impact of n-3 fatty acids on endothelial function: results from human interventions studies. Curr Opin Clin Nutr Metab Care, 14: 121–131, 2011.
39.
FalckJR, KrishnaUM, ReddyYK, KumarPS, ReddyKM, HittnerSB, DeeterC, SharmaKK, GauthierKM, and CampbellWB. Comparison of vasodilatory properties of 14,15-EET analogs: structural requirements for dilation. Am J Physiol Heart Circ Physiol, 284: H337–H349, 2003.
FaresH, LavieCJ, DinicolantonioJJ, O'KeefeJH, and MilaniRV. Omega-3 fatty acids: a growing ocean of choices. Curr Atheroscler Rep, 16: 389, 2014.
42.
FerM, DreanoY, LucasD, CorcosL, SalaunJP, BerthouF, and AmetY. Metabolism of eicosapentaenoic and docosahexaenoic acids by recombinant human cytochromes P450. Arch Biochem Biophys, 471: 116–125, 2008.
43.
FischerD, LandmesserU, SpiekermannS, Hilfiker-KleinerD, HospelyM, MullerM, BusseR, FlemingI, and DrexlerH. Cytochrome P450 2C9 is involved in flow-dependent vasodilation of peripheral conduit arteries in healthy subjects and in patients with chronic heart failure. Eur J Heart Fail, 9: 770–775, 2007.
44.
FischerR, KonkelA, MehlingH, BlosseyK, GapelyukA, WesselN, von SchackyC, DechendR, MullerDN, RotheM, LuftFC, WeylandtK, and SchunckWH. Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway. J Lipid Res, 55: 1150–1164, 2014.
45.
FisslthalerB, HinschN, ChataigneauT, PoppR, KissL, BusseR, and FlemingI. Nifedipine increases cytochrome P4502C expression and EDHF-mediated responses in coronary arteries. Hypertension, 36: 270–275, 2000.
46.
FisslthalerB, MichaelisUR, RandriamboavonjyV, BusseR, and FlemingI. Cytochrome P450 epoxygenases and vascular tone: novel role for HMG-CoA reductase inhibitors in the regulation of CYP 2C expression. Biochim Biophys Acta, 1619: 332–339, 2003.
47.
FisslthalerB, PoppR, KissL, PotenteM, HarderDR, FlemingI, and BusseR. Cytochrome P450 2C is an EDHF synthase in coronary arteries. Nature, 401: 493–497, 1999.
FlieslerSJ and AndersonRE. Chemistry and metabolism of lipids in the vertebrate retina. Prog Lipid Res, 22: 79–131, 1983.
53.
FranklinMR and HathawayLB. 2-Diethylaminoethyl-2,2-diphenylvalerate-HCl (SKF525A) revisited: comparative cytochrome P450 inhibition in human liver microsomes by SKF525A, its metabolites, and SKF-acid and SKF-alcohol. Drug Metab Dispos, 36: 2539–2546, 2008.
54.
FrömelT, JungblutB, HuJ, TrouvainC, Barbosa-SicardE, PoppR, LiebnerS, DimmelerS, HammockBD, and FlemingI. Soluble epoxide hydrolase regulates hematopoietic progenitor cell function via generation of fatty acid diols. Proc Natl Acad Sci U S A, 109: 9995–10000, 2012.
55.
FrömelT, KohlstedtK, PoppR, YinX, Barbosa-SicardE, ThomasAC, LiebertzR, MayrM, and FlemingI. Cytochrome P4502S1: a novel monocyte/macrophage fatty acid epoxygenase in human atherosclerotic plaques. Basic Res Cardiol, 108: 1–12, 2013.
56.
GauthierKM, DeeterC, KrishnaUM, ReddyYK, BondlelaM, FalckJR, and CampbellWB. 14,15-Epoxyeicosa-5(Z)-enoic acid: a selective epoxyeicosatrienoic acid antagonist that inhibits endothelium-dependent hyperpolarization and relaxation in coronary arteries. Circ Res, 90: 1028–1036, 2002.
57.
GraierWF, SimecekS, and SturekM. Cytochrome P450 mono-oxygenase-regulated signalling of Ca2+ entry in human and bovine endothelial cells. J Physiol (Lond), 482: 259–274, 1995.
58.
HarrisTR and HammockBD. Soluble epoxide hydrolase: gene structure, expression and deletion. Gene, 526: 61–74, 2013.
59.
HerbertSP, HuiskenJ, KimTN, FeldmanME, HousemanBT, WangRA, ShokatKM, and StainierDY. Arterial-venous segregation by selective cell sprouting: an alternative mode of blood vessel formation. Science, 326: 294–298, 2009.
60.
HerculeHC, SalanovaB, EssinK, HoneckH, FalckJR, SausbierM, RuthP, SchunckWH, LuftFC, and GollaschM. The vasodilator 17,18-epoxyeicosatetraenoic acid targets the pore-forming BK alpha channel subunit in rodents. Exp Physiol, 92: 1067–1076, 2007.
61.
HilligT, KrustrupP, FlemingI, OsadaT, SaltinB, and HellstenY. Cytochrome P450 2C9 plays an important role in the regulation of exercise-induced skeletal muscle blood flow and oxygen uptake in humans. J Physiol (Lond), 546: 307–314, 2003.
62.
HondaHM, LeitingerN, FrankelM, GoldhaberJI, NatarajanR, NadlerJL, WeissJN, and BerlinerJA. Induction of monocyte binding to endothelial cells by MM-LDL: role of lipoxygenase metabolites. Arterioscler Thromb Vasc Biol, 19: 680–686, 1999.
63.
HoshiT, WissuwaB, TianY, TajimaN, XuR, BauerM, HeinemannSH, and HouS. Omega-3 fatty acids lower blood pressure by directly activating large-conductance Ca2+-dependent K+ channels. Proc Natl Acad Sci U S A, 110: 4816–4821, 2013.
64.
HuJ, PoppR, FrömelT, EhlingM, AwwadK, AdamsRH, HammesHP, and FlemingI. Müller glia cells regulate Notch signaling and retinal angiogenesis via the generation of 19,20-dihydroxydocosapentaenoic acid. J Exp Med, 211: 281–295, 2014.
65.
ImigJD. Epoxide hydrolase and epoxygenase metabolites as therapeutic targets for renal diseases. Am J Physiol Renal Physiol, 289: F496–F503, 2005.
66.
ImigJD. Epoxides and soluble epoxide hydrolase in cardiovascular physiology. Physiol Rev, 92: 101–130, 2012.
67.
ImigJD. Epoxyeicosatrienoic acids, 20-hydroxyeicosatetraenoic acid, and renal microvascular function. Prostaglandins Other Lipid Mediat, 104–105: 2–7, 2013.
68.
ImigJD, FalckJR, WeiS, and CapdevilaJH. Epoxygenase metabolites contribute to nitric oxide-independent afferent arteriolar vasodilation in response to bradykinin. J Vasc Res, 38: 247–255, 2001.
69.
ImigJD and HammockBD. Soluble epoxide hydrolase as a therapeutic target for cardiovascular diseases. Nat Rev Drug Discov, 8: 794–805, 2009.
70.
InceogluB, SchmelzerKR, MorisseauC, JinksSL, and HammockBD. Soluble epoxide hydrolase inhibition reveals novel biological functions of epoxyeicosatrienoic acids (EETs). Prostaglandins Other Lipid Mediat, 82: 42–49, 2007.
71.
JordiM, AleixS, RichardK, RaimonF, NúriaP, JosefaG, DaianaI, MercedesH, EmilioR, and LluísM. Increasing long-chain n-3PUFA consumption improves small peripheral artery function in patients at intermediate-high cardiovascular risk. J Nutr Biochem, 25: 642–646, 2014.
72.
JoukovV, PajusolaK, KaipainenA, ChilovD, LahtinenI, KukkE, SakselaO, KalkkinenN, and AlitaloK. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J, 15: 1751, 1996.
73.
JumpDB. The biochemistry of n-3 polyunsaturated fatty acids. J Biol Chem, 277: 8755–8758, 2002.
74.
JungO, BrandesRP, KimIH, SchwedaF, SchmidtR, HammockBD, BusseR, and FlemingI. Soluble epoxide hydrolase is a main effector of angiotensin II-induced hypertension. Hypertension, 45: 759–765, 2005.
75.
KangJX, WangJ, WuL, and KangZB. Transgenic mice: fat-1 mice convert n-6 to n-3 fatty acids. Nature, 427: 504, 2004.
76.
KararaA, DishmanE, FalckJR, and CapdevilaJH. Endogenous epoxyeicosatrienoyl-phospholipids. A novel class of cellular glycerolipids containing epoxidized arachidonate moieties. J Biol Chem, 266: 7561–7569, 1991.
77.
KeserüB, Barbosa-SicardE, PoppR, FisslthalerB, DietrichA, GudermannT, HammockBD, FalckJR, WeissmannN, BusseR, and FlemingI. Epoxyeicosatrienoic acids and the soluble epoxide hydrolase are determinants of pulmonary artery pressure and the acute hypoxic pulmonary vasoconstrictor response. FASEB J, 22: 4306–4315, 2008.
78.
KeserüB, Barbosa-SicardE, SchermulyRT, TanakaH, HammockBD, WeissmannN, FisslthalerB, and FlemingI. Hypoxia-induced pulmonary hypertension: comparison of soluble epoxide hydrolase deletion vs. inhibition. Cardiovasc Res, 85: 232–240, 2010.
79.
KhojastehS, PrabhuS, KennyJ, HalladayJ, and LuA. Chemical inhibitors of cytochrome P450 isoforms in human liver microsomes: a re-evaluation of P450 isoform selectivity. Eur J Drug Metab Pharmacokinet, 36: 1–16, 2011.
80.
KiddPM. Omega-3 DHA and EPA for cognition, behavior, and mood: clinical findings and structural-functional synergies with cell membrane phospholipids. Altern Med Rev, 12: 207–227, 2007.
81.
KimHY. Novel metabolism of docosahexaenoic acid in neural cells. J Biol Chem, 282: 18661–18665, 2007.
82.
KimJD, KangY, KimJ, PapangeliI, KangH, WuJ, ParkH, NadelmannE, RocksonSG, ChunHJ, and JinSW. Essential role of apelin signaling during lymphatic development in zebrafish. Arterioscler Thromb Vasc Biol, 34: 338–345, 2014.
83.
KimW, FanYY, BarhoumiR, SmithR, McMurrayDN, and ChapkinRS. n-3 polyunsaturated fatty acids suppress the localization and activation of signaling proteins at the immunological synapse in murine CD4+ T cells by affecting lipid raft formation. J Immunol, 181: 6236–6243, 2008.
84.
KitsonAP, StarkKD, and DuncanRE. Enzymes in brain phospholipid docosahexaenoic acid accretion: a PL-ethora of potential PL-ayers. Prostaglandins Leukot Essent Fatty Acids, 87: 1–10, 2012.
85.
KnappHR and FitzGeraldGA. The antihypertensive effects of fish oil. A controlled study of polyunsaturated fatty acid supplements in essential hypertension. N Engl J Med, 320: 1037–1043, 1989.
86.
KonkelA and SchunckWH. Role of cytochrome P450 enzymes in the bioactivation of polyunsaturated fatty acids. Biochim Biophys Acta, 1814: 210–222, 2011.
87.
KumarKV, RaoSM, GayaniR, MohanIK, and NaiduMUR. Oxidant stress and essential fatty acids in patients with risk and established ARDS. Clin Chim Acta, 298: 111–120, 2000.
88.
LaiLH, WangRX, JiangWP, YangXJ, SongJP, LiXR, and TaoG. Effects of docosahexaenoic acid on large-conductance Ca2+-activated K+ channels and voltage-dependent K+ channels in rat coronary artery smooth muscle cells. Acta Pharmacol Sin, 30: 314–320, 2009.
89.
LauterbachB, Barbosa-SicardE, WangMH, HoneckH, KargelE, TheuerJ, SchwartzmanML, HallerH, LuftFC, GollaschM, and SchunckWH. Cytochrome P450-dependent eicosapentaenoic acid metabolites are novel BK channel activators. Hypertension, 39: 609–613, 2002.
90.
LeeS, ChenTT, BarberCL, JordanMC, MurdockJ, DesaiS, FerraraN, NagyA, RoosKP, and Iruela-ArispeML. Autocrine VEGF signaling is required for vascular homeostasis. Cell, 130: 691–703, 2007.
91.
LeeSM and AnWS. Cardioprotective effects of omega −3 PUFAs in chronic kidney disease. Biomed Res Int, 2013: 712949, 2013.
92.
LeonardAE, PereiraSL, SprecherH, and HuangYS. Elongation of long-chain fatty acids. Prog Lipid Res, 43: 36–54, 2004.
93.
LeventalI, GrzybekM, and SimonsK. Greasing their way: lipid modifications determine protein association with membrane rafts. Biochemistry, 49: 6305–6316, 2010.
94.
LiuJY, LiN, YangJ, LiN, QiuH, AiD, ChiamvimonvatN, ZhuY, and HammockBD. Metabolic profiling of murine plasma reveals an unexpected biomarker in rofecoxib-mediated cardiovascular events. Proc Natl Acad Sci U S A, 107: 17017–17022, 2010.
95.
LootAE, PoppR, FisslthalerB, VriensJ, NiliusB, and FlemingI. Role of cytochrome P450-dependent transient receptor potential V4 activation in flow-induced vasodilatation. Cardiovasc Res, 80: 445–452, 2008.
96.
LovegroveJA and GriffinBA. The acute and long-term effects of dietary fatty acids on vascular function in health and disease. Curr Opin Clin Nutr Metab Care, 16: 162–167, 2013.
97.
LuT, VanRollinsM, and LeeHC. Stereospecific activation of cardiac ATP-sensitive K+ channels by epoxyeicosatrienoic acids: a structural determinant study. Mol Pharmacol, 62: 1076–1083, 2002.
98.
LuriaA, WeldonSM, KabcenellAK, IngrahamRH, MateraD, JiangH, GillR, MorisseauC, NewmanJW, and HammockBD. Compensatory mechanism for homeostatic blood pressure regulation in Ephx2 gene-disrupted mice. J Biol Chem, 282: 2891–2898, 2007.
99.
MadanayakeTW, FidlerTP, FresquezTW, BajajN, and RowlandAM. Cytochrome P450 2S1 depletion enhances cell proliferation and migration in bronchial epithelial cells, in part, through modulation of prostaglandin E2 synthesis. Drug Metab Dispos, 40: 2119–2125, 2012.
100.
MaddenJ, WilliamsCM, CalderPC, LietzG, MilesEA, CordellH, MathersJC, and MinihaneAM. The impact of common gene variants on the response of biomarkers of cardiovascular disease (CVD) risk to increased fish oil fatty acids intakes. Annu Rev Nutr, 31: 203–234, 2011.
101.
McSherryIN, SandowSL, CampbellWB, FalckJR, HillMA, and DoraKA. A role for heterocellular coupling and EETs in dilation of rat cremaster arteries. Microcirculation, 13: 119–130, 2006.
102.
MedhoraM, DanielsJ, MundeyK, FisslthalerB, BusseR, JacobsER, and HarderDR. Epoxygenase-driven angiogenesis in human lung microvascular endothelial cells. Am J Physiol Heart Circ Physiol, 284: H215–H224, 2003.
103.
MerleBM, BenlianP, PucheN, BassolsA, DelcourtC, and SouiedEH. Circulating omega-3 fatty acids and neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci, 55: 2010–2019, 2014.
104.
MichaelisUR, FisslthalerB, MedhoraM, HarderD, FlemingI, and BusseR. Cytochrome P450 2C9-derived epoxyeicosatrienoic acids induce angiogenesis via cross-talk with the epidermal growth factor receptor (EGFR). FASEB J, 17: 770–772, 2003.
105.
MichaelisUR and FlemingI. From endothelium-derived hyperpolarizing factor (EDHF) to angiogenesis: epoxyeicosatrienoic acids (EETs) and cell signaling. Pharmacol Ther, 111: 584–595, 2006.
106.
MichaelisUR, XiaN, Barbosa-SicardE, FalckJR, BusseR, and FlemingI. Role of cytochrome P450 2C epoxygenases in hypoxia-induced cell migration and angiogenesis in retinal endothelial cells. Invest Ophthalmol Vis Sci, 49: 1242–1247, 2008.
107.
MoghaddamMF, GrantDF, CheekJM, GreeneJF, WilliamsonKC, and HammockBD. Bioactivation of leukotoxins to their toxic diols by epoxide hydrolase. Nat Med, 3: 562–566, 1997.
108.
MorinC, SiroisM, EchaveV, AlbadineR, and RousseauE. 17,18-Epoxyeicosatetraenoic acid targets PPARγ and p38 mitogen-coactivated protein kinase to mediate its anti-inflammatory effects in the lung. Am J Respir Cell Mol Biol, 43: 564–575, 2010.
109.
MorisseauC and HammockBD. Impact of soluble epoxide hydrolase and epoxyeicosanoids on human health. Annu Rev Pharmacol Toxicol, 53: 37–58, 2013.
110.
MorisseauC, InceogluB, SchmelzerK, TsaiHJ, JinksSL, HegedusCM, and HammockBD. Naturally occurring monoepoxides of eicosapentaenoic acid and docosahexaenoic acid are bioactive antihyperalgesic lipids. J Lipid Res, 51: 3481–3490, 2010.
111.
MullerDN, SchmidtC, Barbosa-SicardE, WellnerM, GrossV, HerculeH, MarkovicM, HoneckH, LuftFC, and SchunckWH. Mouse Cyp4a isoforms: enzymatic properties, gender- and strain-specific expression, and role in renal 20-hydroxyeicosatetraenoic acid formation. Biochem J, 403: 109–118, 2007.
112.
MunzenmaierDH and HarderDR. Cerebral microvascular endothelial cell tube formation: role of astrocytic epoxyeicosatrienoic acid release. Am J Physiol Heart Circ Physiol, 278: H1163–H1167, 2000.
113.
NakamuraT, BrattonDL, and MurphyRC. Analysis of epoxyeicosatrienoic and monohydroxyeicosatetraenoic acids esterified to phospholipids in human red blood cells by electrospray tandem mass spectrometry. J Mass Spectrom, 32: 888–896, 1997.
114.
NakayamaK, NittoT, InoueT, and NodeK. Expression of the cytochrome P450 epoxygenase CYP2J2 in human monocytic leukocytes. Life Sci, 83: 339–345, 2008.
115.
NewmanJW, MorisseauC, and HammockBD. Epoxide hydrolases: their roles and interactions with lipid metabolism. Prog Lipid Res, 44: 1–51, 2005.
116.
NguyenLN, MaD, ShuiG, WongP, Cazenave-GassiotA, ZhangX, WenkMR, GohEL, and SilverDL. Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Nature, 509: 503–506, 2014.
117.
NodeK, HuoY, RuanX, YangB, SpieckerM, LeyK, ZeldinDC, and LiaoJK. Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids. Science, 285: 1276–1279, 1999.
118.
NodeK, RuanXL, DaiJ, YangSX, GrahamL, ZeldinDC, and LiaoJK. Activation of Gαs mediates induction of tissue-type plasminogen activator gene transcription by epoxyeicosatrienoic acids. J Biol Chem, 276: 15983–15989, 2001.
119.
NordingML, YangJ, GeorgiK, Hegedus KarbowskiC, GermanJB, WeissRH, HoggRJ, TryggJ, HammockBD, and ZivkovicAM. Individual variation in lipidomic profiles of healthy subjects in response to omega-3 fatty acids. PLoS One, 8: e76575, 2013.
120.
OhDY, TalukdarS, BaeEJ, ImamuraT, MorinagaH, FanW, LiP, LuWJ, WatkinsSM, and OlefskyJM. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell, 142: 687–698, 2010.
121.
OhtoshiK, KanetoH, NodeK, NakamuraY, ShiraiwaT, MatsuhisaM, and YamasakiY. Association of soluble epoxide hydrolase gene polymorphism with insulin resistance in type 2 diabetic patients. Biochem Biophys Res Commun, 331: 347–350, 2005.
122.
OliwEH and BenthinG. On the metabolism of epoxyeicosatrienoic acids by ram seminal vesicles: isolation of 5(6)epoxy-prostaglandin F1α. Biochem Biophys Res Commun, 126: 1090–1096, 1985.
123.
OzkorMA, MurrowJR, RahmanAM, KavtaradzeN, LinJ, ManatungaA, and QuyyumiAA. Endothelium-derived hyperpolarizing factor determines resting and stimulated forearm vasodilator tone in health and in disease. Circulation, 123: 2244–2253, 2011.
ParkHS, KimMS, HuhSH, ParkJ, ChungJ, KangSS, and ChoiEJ. Akt (protein kinase B) negatively regulates SEK1 by means of protein phosphorylation. J Biol Chem, 277: 2573–2578, 2002.
126.
PascualJMS, McKenzieA, YankaskasJR, FalckJR, and ZeldinDC. Epoxygenase metabolites of arachidonic acid affect electrophysiologic properties of rat tracheal epithelial cells. J Pharmacol Exp Ther, 286: 772–779, 1998.
127.
PennJS, TolmanBL, and LoweryLA. Variable oxygen exposure causes preretinal neovascularization in the newborn rat. Invest Ophthalmol Vis Sci, 34: 576–585, 1993.
128.
PfisterSL, GauthierKM, and CampbellWB. Vascular pharmacology of epoxyeicosatrienoic acids. Adv Pharmacol, 60: 27–59, 2010.
129.
PoppR, BauersachsJ, HeckerM, FlemingI, and BusseR. A transferable, β-naphthoflavone-inducible, hyperpolarizing factor is synthesized by native and cultured porcine coronary endothelial cells. J Physiol (Lond), 497: 699–709, 1996.
130.
PoppR, BrandesRP, OttG, BusseR, and FlemingI. Dynamic modulation of interendothelial gap junctional communication by 11,12-epoxyeicosatrienoic acid. Circ Res, 90: 800–806, 2002.
131.
PotenteM, FisslthalerB, BusseR, and FlemingI. 11,12-Epoxyeicosatrienoic acid-induced inhibition of FOXO factors promotes endothelial proliferation by down-regulating p27Kip1. J Biol Chem, 278: 29619–29625, 2003.
132.
PotenteM, MichaelisUR, FisslthalerB, BusseR, and FlemingI. Cytochrome P450 2C9-induced endothelial cell proliferation involves induction of mitogen-activated protein (MAP) kinase phosphatase-1, inhibition of the c-Jun N-terminal kinase, and up-regulation of cyclin D1. J Biol Chem, 277: 15671–15676, 2002.
133.
PozziA, Macias-PerezI, AbairT, WeyS, SuY, ZentR, FalkJR, and CapdevilaJH. Charaterization of 5,6-and 8,9-epoxyeicosatrienoic acids (5,6- and 8,9-EET) as potent in vivo angiogenic lipids. J Biol Chem, 280: 27138–27146, 2005.
134.
PrattPF, LiP, HillardCJ, KurianJ, and CampbellWB. Endothelium-independent, ouabain-sensitive relaxation of bovine coronary arteries by EETs. Am J Physiol Heart Circ Physiol, 280: H1113–H1121, 2001.
135.
QuinlanGJ, LambNJ, EvansTW, and GutteridgeJM. Plasma fatty acid changes and increased lipid peroxidation in patients with adult respiratory distress syndrome. Crit Care Med, 24: 241–246, 1996.
136.
RosettiC and PastorinoC. Polyunsaturated and saturated phospholipids in mixed bilayers: a study from the molecular scale to the lateral lipid organization. J Phys Chem B, 115: 1002–1013, 2011.
137.
RussoGL. Dietary n-6 and n-3 polyunsaturated fatty acids: from biochemistry to clinical implications in cardiovascular prevention. Biochem Pharmacol, 77: 937–946, 2009.
138.
SamokhvalovV, AlsalehN, El-SikhryHE, JamiesonKL, ChenCB, LopaschukDG, CarterC, LightPE, ManneR, FalckJR, and SeubertJM. Epoxyeicosatrienoic acids protect cardiac cells during starvation by modulating an autophagic response. Cell Death Dis, 4: e885, 2013.
139.
SandowSL and HillCE. The incidence of myoendothelial gap junctions in the proximal and distal mesenteric arteries of the rat is suggestive of a role in EDHF mediated responses. Circ Res, 86: 341–346, 2000.
140.
SandowSL, TareM, ColemanHA, HillCE, and ParkingtonHC. Involvement of myoendothelial gap junctions in the actions of endothelium-derived hyperpolarizing factor. Circ Res, 90: 1108–1113, 2002.
141.
SantoroN, CaprioS, GianniniC, KimG, KursaweR, PierpontB, ShawMM, and FeldsteinAE. Oxidized fatty acids: a potential pathogenic link between Fatty liver and type 2 diabetes in obese adolescents?. Antioxid Redox Signal, 20: 383–389, 2014.
142.
SapiehaP, JoyalJS, RiveraJC, Kermorvant-DucheminE, SennlaubF, HardyP, LachapelleP, and ChemtobS. Retinopathy of prematurity: understanding ischemic retinal vasculopathies at an extreme of life. J Clin Invest, 120: 3022–3032, 2010.
143.
SapiehaP, StahlA, ChenJ, SeawardMR, WillettKL, KrahNM, DennisonRJ, ConnorKM, AdermanCM, LiclicanE, CarughiA, PerelmanD, KanaokaY, SangiovanniJP, GronertK, and SmithLE. 5-Lipoxygenase metabolite 4-HDHA is a mediator of the antiangiogenic effect of omega-3 polyunsaturated fatty acids. Sci Transl Med, 3: 69ra12, 2011.
144.
SchuchardtJP, SchmidtS, KresselG, WillenbergI, HammockBD, HahnA, and SchebbNH. Modulation of blood oxylipin levels by long-chain omega-3 fatty acid supplementation in hyper- and normolipidemic men. Prostaglandins Leukot Essent Fatty Acids, 90: 27–37, 2014.
145.
SekiH, TaniY, and AritaM. Omega-3 PUFA derived anti-inflammatory lipid mediator resolvin E1. Prostaglandins Other Lipid Mediat, 89: 126–130, 2009.
146.
SerhanCN. Pro-resolving lipid mediators are leads for resolution physiology. Nature, 510: 92–101, 2014.
147.
SerhanCN and PetasisNA. Resolvins and protectins in inflammation resolution. Chem Rev, 111: 5922–5943, 2011.
148.
ShaikhSR. Biophysical and biochemical mechanisms by which dietary N-3 polyunsaturated fatty acids from fish oil disrupt membrane lipid rafts. J Nutr Biochem, 23: 101–105, 2012.
ShivacharAC, WilloughbyKA, and EllisEF. Effect of protein kinase C modulators on 14,15-epoxyeicosatrienoic acid incorporation into astroglial phospholipids. J Neurochem, 65: 338–346, 1995.
151.
SinalCJ, MiyataM, TohkinM, NagataK, BendJR, and GonzalezFJ. Targeted disruption of soluble epoxide hydrolase reveals a role in blood pressure regulation. J Biol Chem, 275: 40504–40510, 2000.
152.
SmithLE, WesolowskiE, McLellanA, KostykSK, D'AmatoR, SullivanR, and D'AmorePA. Oxygen-induced retinopathy in the mouse. Invest Ophthalmol Vis Sci, 35: 101–111, 1994.
153.
SnyderJL, KearnsCA, and AppelB. Fbxw7 regulates Notch to control specification of neural precursors for oligodendrocyte fate. Neural Dev, 7: 15, 2012.
154.
SouiedEH, DelcourtC, QuerquesG, BassolsA, MerleB, ZourdaniA, SmithT, and BenlianP. Oral docosahexaenoic acid in the prevention of exudative age-related macular degeneration: the nutritional AMD treatment 2 study. Ophthalmology, 120: 1619–1631, 2013.
155.
SpectorAA and NorrisAW. Action of epoxyeicosatrienoic acids on cellular function. Am J Physiol Cell Physiol, 292: C996–C1012, 2007.
156.
SpiteM, ClariaJ, and SerhanCN. Resolvins, specialized proresolving lipid mediators, and their potential roles in metabolic diseases. Cell Metab, 19: 21–36, 2014.
157.
SpitzmaulG, GumilarF, DilgerJP, and BouzatC. The local anaesthetics proadifen and adiphenine inhibit nicotinic receptors by different molecular mechanisms. Br J Pharmacol, 157: 804–817, 2009.
158.
SprongH, van der SluijsP, and vanMG. How proteins move lipids and lipids move proteins. Nat Rev Mol Cell Biol, 2: 504–513, 2001.
159.
StackerSA, WilliamsSP, KarnezisT, ShayanR, FoxSB, and AchenMG. Lymphangiogenesis and lymphatic vessel remodelling in cancer. Nat Rev Cancer, 14: 159–172, 2014.
160.
TaddeiS, VersariD, CiprianoA, GhiadoniL, GalettaF, FranzoniF, MagagnaA, VirdisA, and SalvettiA. Identification of a cytochrome P450 2C9-derived endothelium-derived hyperpolarizing factor in essential hypertensive patients. J Am Coll Cardiol, 48: 508–515, 2006.
161.
TalukdarS, OlefskyJM, and OsbornO. Targeting GPR120 and other fatty acid-sensing GPCRs ameliorates insulin resistance and inflammatory diseases. Trends Pharmacol Sci, 32: 543–550, 2011.
162.
TikhonenkoM, LydicTA, OpreanuM, LiCS, BozackS, McSorleyKM, SochackiAL, FaberMS, HazraS, DuclosS, GuberskiD, ReidGE, GrantMB, and BusikJV. N-3 polyunsaturated fatty acids prevent diabetic retinopathy by inhibition of retinal vascular damage and enhanced endothelial progenitor cell reparative function. PLoS One, 8: e55177, 2013.
163.
UluA, HarrisTR, MorisseauC, MiyabeC, InoueH, SchusterG, DongH, IosifAM, LiuJY, WeissRH, ChiamvimonvatN, ImigJD, and HammockBD. Anti-inflammatory effects of omega-3 polyunsaturated fatty acids and soluble epoxide hydrolase inhibitors in angiotensin-II-dependent hypertension. J Cardiovasc Pharmacol, 62: 285–297, 2013.
164.
UranoY, HayashiI, IsooN, ReidPC, ShibasakiY, NoguchiN, TomitaT, IwatsuboT, HamakuboT, and KodamaT. Association of active gamma-secretase complex with lipid rafts. J Lipid Res, 46: 904–912, 2005.
165.
VanRollinsM, KaduceTL, FangX, KnappHR, and SpectorAA. Arachidonic acid diols produced by cytochrome P-450 monooxygenases are incorporated into phospholipids of vascular endothelial cells. J Biol Chem, 271: 14001–14009, 1996.
166.
VirdisA, CetaniF, GiannarelliC, BantiC, GhiadoniL, AmbroginiE, CarraraD, PincheraA, TaddeiS, BerniniG, and MarcocciC. The sulfaphenazole-sensitive pathway acts as a compensatory mechanism for impaired nitric oxide availability in patients with primary hyperparathyroidism. Effect of surgical treatment. J Clin Endocrinol Metab, 95: 920–927, 2010.
167.
VriensJ, OwsianikG, FisslthalerB, SuzukiM, JanssensA, VoetsT, MorisseauC, HammockBD, FlemingI, BusseR, and NiliusB. Modulation of the Ca2+ permeable cation channel TRPV4 by cytochrome P450 epoxygenases in vascular endothelium. Circ Res, 97: 908–915, 2005.
168.
WadaM, DeLongCJ, HongYH, RiekeCJ, SongI, SidhuRS, YuanC, WarnockM, SchmaierAH, YokoyamaC, SmythEM, WilsonSJ, FitzGeraldGA, GaravitoRM, SuiDX, ReganJW, and SmithWL. Enzymes and receptors of prostaglandin pathways with arachidonic acid-derived versus eicosapentaenoic acid-derived substrates and products. J Biol Chem, 282: 22254–22266, 2007.
169.
WangMH, Brand-SchieberE, ZandBA, NguyenX, FalckJR, BaluN, and SchwartzmanML. Cytochrome P450-derived arachidonic acid metabolism in the rat kidney: characterization of selective inhibitors. J Pharmacol Exp Ther, 284: 966–973, 1998.
170.
WangRX, ChaiQ, LuT, and LeeHC. Activation of vascular BK channels by docosahexaenoic acid is dependent on cytochrome P450 epoxygenase activity. Cardiovasc Res, 90: 344–352, 2011.
WangY, WeiX, XiaoX, HuiR, CardJW, CareyMA, WangDW, and ZeldinDC. Arachidonic acid epoxygenase metabolites stimulate endothelial cell growth and angiogenesis via mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt signaling pathways. J Pharmacol Exp Ther, 314: 522–532, 2005.
173.
WassallSR and StillwellW. Docosahexaenoic acid domains: the ultimate non-raft membrane domain. Chem Phys Lipids, 153: 57–63, 2008.
174.
WatanabeH, VriensJ, PrenenJ, DroogmansG, VoetsT, and NiliusB. Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels. Nature, 424: 434–438, 2003.
175.
WeblerAC, PoppR, KorffT, MichaelisUR, UrbichC, BusseR, and FlemingI. Cytochrome P450 2C9-induced angiogenesis is dependent on EphB4. Arterioscler Thromb Vasc Biol, 28: 1123–1129, 2008.
176.
WeintraubNL, FangX, KaduceTL, VanRollinsM, ChatterjeeP, and SpectorAA. Potentiation of endothelium-dependent relaxation by epoxyeicosatrienoic acids. Circ Res, 81: 258–267, 1997.
177.
WestphalC, KonkelA, and SchunckWH. CYP-eicosanoids—a new link between omega-3 fatty acids and cardiac disease?. Prostaglandins Other Lipid Mediat, 96: 99–108, 2011.
178.
WiechaJ, MunzB, WuY, NollT, TillmannsH, and WaldeckerB. Blockade of Ca2+-activated K+ channels inhibits proliferation of human endothelial cells induced by basic fibroblast growth factor. J Vasc Res, 35: 363–371, 1998.
179.
WileyDM, KimJD, HaoJ, HongCC, BautchVL, and JinSW. Distinct signalling pathways regulate sprouting angiogenesis from the dorsal aorta and the axial vein. Nat Cell Biol, 13: 686–692, 2011.
180.
WilliamsJA, BattenSE, HarrisM, RockettBD, ShaikhSR, StillwellW, and WassallSR. Docosahexaenoic and eicosapentaenoic acids segregate differently between raft and nonraft domains. Biophys J, 103: 228–237, 2012.
181.
WrayJ and Bishop-BaileyD. Epoxygenases and peroxisome proliferator-activated receptors in mammalian vascular biology. Exp Physiol, 93: 148–154, 2008.
182.
WrayJA, SugdenMC, ZeldinDC, GreenwoodGK, SamsuddinS, Miller-DegraffL, BradburyJA, HolnessMJ, WarnerTD, and Bishop-BaileyD. The epoxygenases CYP2J2 activates the nuclear receptor PPARα in vitro and in vivo. PLoS One, 4: e7421, 2009.
183.
YamadaT, MorisseauC, MaxwellJE, ArgiriadiMA, ChristiansonDW, and HammockBD. Biochemical evidence for the involvement of tyrosine in epoxide activation during the catalytic cycle of epoxide hydrolase. J Biol Chem, 275: 23082–23088, 2000.
184.
YangW, TunikiVR, AnjaiahS, FalckJR, HillardCJ, and CampbellWB. Characterization of epoxyeicosatrienoic acid binding site in U937 membranes using a novel radiolabeled agonist, 20-125I-14,15-epoxyeicosa-8(Z)-enoic acid. J Pharmacol Exp Ther, 324: 1019–1027, 2008.
185.
YeD, ZhangD, OltmanC, DellspergerK, LeeHC, and VanRollinsM. Cytochrome p-450 epoxygenase metabolites of docosahexaenoate potently dilate coronary arterioles by activating large-conductance calcium-activated potassium channels. J Pharmacol Exp Ther, 303: 768–776, 2002.
186.
YeD, ZhouW, and LeeHC. Activation of rat mesenteric arterial KATP channels by 11,12-epoxyeicosatrienoic acid. Am J Physiol Heart Circ Physiol, 288: H358–H364, 2005.
187.
YeD, ZhouW, LuT, JagadeeshSG, FalckJR, and LeeHC. Mechanism of rat mesenteric arterial KATP channel activation by 14,15-epoxyeicosatrienoic acid. Am J Physiol Heart Circ Physiol, 290: H1326–H1336, 2006.
Zemski BerryKA, GordonWC, MurphyRC, and BazanNG. Spatial organization of lipids in the human retina and optic nerve by MALDI imaging mass spectrometry. J Lipid Res, 55: 504–515, 2014.
192.
ZhangC and HarderDR. Cerebral capillary endothelial cell mitogenesis and morphogenesis induced by astrocytic epoxyeicosatrienoic acid. Stroke, 33: 2957–2964, 2002.
193.
ZhangG, PanigrahyD, MahakianLM, YangJ, LiuJY, Stephen LeeKS, WetterstenHI, UluA, HuX, TamS, HwangSH, InghamES, KieranMW, WeissRH, FerraraKW, and HammockBD. Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis. Proc Natl Acad Sci U S A, 110: 6530–6535, 2013.
194.
ZhangY, OltmanCL, LuT, LeeHC, DellspergerKC, and VanRollinsM. EET homologs potently dilate coronary microvessels and activate BK(Ca) channels. Am J Physiol Heart Circ Physiol, 280: H2430–H2440, 2001.
195.
ZhaoG, WangJ, XuX, JingY, TuL, LiX, ChenC, CianfloneK, WangP, DackorRT, ZeldinDC, and WangDW. Epoxyeicosatrienoic acids protect rat hearts against tumor necrosis factor-α-induced injury. J Lipid Res, 53: 456–466, 2012.
196.
ZhengX, ZinkevichNS, GebremedhinD, GauthierKM, NishijimaY, FangJ, WilcoxDA, CampbellWB, GuttermanDD, and ZhangDX. Arachidonic acid-induced dilation in human coronary arterioles: convergence of signaling mechanisms on endothelial TRPV4-mediated Ca2+ entry. J Am Heart Assoc, 2: e000080, 2013.
197.
ZhuY, SchieberEB, McGiffJC, and BalazyM. Identification of arachidonate P-450 metabolites in human platelet phospholipids. Hypertension, 25: 854–859, 1995.
198.
ZouAP, FlemingJT, FalckJR, JacobsER, GebremedhinD, HarderDR, and RomanRJ. Stereospecific effects of epoxyeicosatrienoic acids on renal vascular tone and K+-channel activity. Am J Physiol Renal Physiol, 270: F822–F832, 1996.
199.
ZygmuntPM and HögestättED. Role of potassium channels in endothelium-dependent relaxation resistant to nitroarginine in the rat hepatic artery. Br J Pharmacol, 117: 1600–1606, 1996.
