Eicosanoids and Iso-Eicosanoids: Constitutive, Inducible and Transcellular Biosynthesis in Vascular Disease

Introuduction

Current understanding of the mechanisms underlying plaque development (1-3) assigns a key role to oxidative modifications of specific phospholipids that are carried into the subendothelial space with low-density lipoproteins (LDL). These variably oxidized lipids in turn trigger a chronic inflammatory response, largely orchestrated by monocytes/macrophages (1-3). Thrombotic occlusion of a major coronary or cerebral vessel can complicate the sudden fissuring or rupture of a plaque and lead to myocardial infarction or ischemic stroke, respectively. The determinants of lipid oxidation, plaque fragility and of the hemostatic response to plaque rupture, as well as the hemodynamic factors influencing the multifactorial process of atherothrombosis represent targets of pharmacological interventions aimed at reducing the risk of cardiovascular and cerebrovascular complications.

The oxidative modifications of the arachidonic acid backbone, that lead to the formation of enzymatic (eicosanoids) and non-enzymatic (iso-eicosanoids) derivatives (Fig. 1), can provide autacoid mechanisms modulating activation of the major cellular players of atherothrombosis, including platelets, endothelial cells, neutrophils and monocytes/macrophages (4-7). The remarkable clinical effects of low-dose aspirin in reducing the risk of stroke and myocardial infarction by 20 to 50% in various clinical settings (8) provide perhaps the most convincing evidence for the pathophysiologic importance of eicosanoid mechanisms in modulating the thrombotic outcome of plaque fissuring. That interference with a single mechanism of amplification of platelet activation, such as that provided by thromboxane (TX) A₂-thromboxane receptor (TP) interactions on the platelet membrane, can lead to clinically detectable consequences is perhaps surprising, but certainly encouraging in the search of novel targets for pharmacological intervention.

Considerable progress has been made in the eicosanoid field during the last ten years, well beyond the thromboxane/prostacyclin balance hypothesis (9), with the elucidation of at least three distinct modalities of eicosanoid biosynthesis, i.e., constitutive, inducible and transcellular. In this review, we shall discuss the molecular, cellular and pharmacological aspects of eicosanoid and iso-eicosanoid biosynthesis as they relate to the multifactorial process of atherothrombosis, with the aim of suggesting novel pathophysiologic mechanisms as well as potential therapeutic targets.

• References

• 1 Navab M, Berliner JA, Watson AD, Hama SY, Territo MC, Lusis AJ, Shih DM. et al. The yin and yang of oxidation in the development of the fatty streak. A review based on the 1994 George Lyman Duff Memorial Lecture. Arterioscler Thromb Vasc Biol 1996; 16: 831-42.
• 2 Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989; 320: 915-24.
• 3 Witztum JL, Steinberg D. Role of oxidized low density lipoprotein in atherogenesis. J Clin Invest 1991; 88: 1785-92.
• 4 FitzGerald GA. Mechanisms of platelet activation: thromboxane A2 as an amplifying signal for other agonists. Am J Cardiol 1991; 68: 11B-15B.
• 5 Marcus AJ. Multicellular eicosanoid and other metabolic interactions of platelets and other cells. In Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 3rd edition. Colman RW, Hirsh J, Marder VJ, Salz-man EW. eds. Lippincott Company; Philadelphia: 1994. pp. 590-602.
• 6 Smith WL, Garavito RM, DeWitt DL. Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and -2. J Biol Chem 1996; 271: 33157-60.
• 7 Patrono C, FitzGerald GA. Isoprostanes: potential markers of oxidant stress in atherothrombotic disease. Arterioscler Thromb Vasc Biol 1997; 17: 2309-15.
• 8 Patrono C. Aspirin as an antiplatelet drug. New Engl J Med 1994; 330: 1287-94.
• 9 Moncada S, Vane JR. Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane-A₂ and prostacyclin. Pharmacol Rev 1978; 30: 293-331.
• 10 Dennis EA. Diversity of group types, regulation and function of phospholipase A₂ . J Biol Chem 1994; 269: 13057-60.
• 11 Dennis EA. The growing phospholipase A₂ superfamily of signal transduction enzymes. Trends Biochem Sci 1997; 22: 1-2.
• 12 Tanabe T, Ullrich V. Prostacyclin and thromboxane synthases. J Lipid Mediators Cell Signalling 1995; 12: 243-55.
• 13 Haurand M, Ullrich V. Isolation and characterization of thromboxane synthase from human platelets as a cytochrome P-450. J Biol Chem 1985; 260: 15059-67.
• 14 Shen R-F, Tai HH. Immunoaffinity purification and characterization of thromboxane synthase from porcine lung. J Biol Chem 1986; 261: 11592-9.
• 15 DeWitt D, Smith WL. Purification of prostacyclin synthase from bovine aorta by immunoaffinity chromatography chromatography. Evidence that the enzyme is a hemoprotein. J Biol Chem 1983; 258: 3285-93.
• 16 Baek SJ, Lee K-D, Shen R-F. Genomic structure and polymorphism of the human thromboxane synthase-encoding gene. Gene 1996; 173: 251-6.
• 17 Wang L-H, Chen L. Organization of the gene encoding human prostacyclin synthase. Biochem Biophys Res Commun 1996; 226: 631-7.
• 18 Nakayama T, Soma M, Izumi Y, Kanmatsuse K. Organization of the human prostacyclin synthase gene. Biochem Biophys Res Commun 1996; 221: 803-6.
• 19 Yokoyama C, Yabuki T, Inoue H, Tone Y, Hara S, Hatae T, Nagata M, Takahashi E-I, Tanabe T. Human gene encoding prostacyclin synthase (PTGIS): genomic organization, chromosomal localization, and promoter activity. Genomics 1996; 36: 296-304.
• 20 Urade Y, Watanabe K, Hayaishi O. Prostaglandin D, E, and F synthases. J Lipid Mediators Cell Signalling 1995; 12: 257-73.
• 21 Funk CD. The molecular biology of mammalian lipoxygenases and the quest for eicosanoid function using lipoxygenase-deficient mice. Biochim Biophys Acta 1996; 1304: 65-84.
• 22 Yamamoto S. Mammalian lipoxygenases: molecular and catalytic properties. Prostaglandins Leukotrienes Ess Fatty Acids 1989; 35: 219-29.
• 23 Hamberg M. Stereochemical aspects of fatty acid oxidation: hydroperoxide isomerases. Acta Chem Scand 1996; 50: 219-24.
• 24 Hamberg M, Samuelsson B. On the specificity of the oxygenation of un-saturated fatty acids catalyzed by soybean lipoxidase. J Biol Chem 1967; 242: 5329-35.
• 25 Brady HR, Papayianni A, Serhan CN. Potential vascular roles for lipoxins in the “stop programs” of host defense and inflammation. Trends Cardiovasc Med 1995; 5: 186-92.
• 26 Henderson WR. The role of leukotrienes in inflammation. Ann Int Med 1994; 121: 684-97.
• 27 Rouzer CA, Matsumoto T, Samuelsson B. Single protein from human leukocytes possesses 5-lipoxygenase and leukotriene A4 synthase activities. Proc Natl Acad Sci USA 1986; 83: 857-61.
• 28 Murphy RC, Hammarström S, Samuelsson B. Leukotriene C: a slow reacting substance (SRS) from murine mastocytoma cells. Proc Natl Acad Sci USA 1979; 76: 4275-9.
• 29 Fitzpatrick F, Murphy RC. Cytochrome P-450 metabolism of arachidonic acid: formation and biological actions of “epoxygenase”-derived eicosanoids. Pharmacol Rev 1989; 40: 229-41.
• 30 Schwartzman M, McGiff JC. Renal cytochrome P450 metabolism of arachidonic acid; biochemistry and molecular biology. In Yamamoto S, and Smith WL. (eds) Molecular Biology of the Arachidonic acid Cascade. Elsevier; Amsterdam: 1995. pp. 229-42.
• 31 Harder DR, Navayanan J, Gebremedhin D, Roman RJ. Transduction of physical force by the vascular wall. Role of phospholipase C and cyto-chrome P450 metabolites of arachidonic acid. Trends Cardiovasc Med 199 5: 7-14.
• 32 Anggard E, Larsson C. The sequence of the early steps in the metabolism of prostaglandin E₁ . Eur J Pharmacol 1971; 14: 66-70.
• 33 Patrono C, Ciabattoni G, Pugliese F, Pierucci A, Blair I, FitzGerald GA. Estimated rate of thromboxane secretion into the circulation of normal humans. J Clin Invest 1986; 72: 590-4.
• 34 Roberts II RJ, Sweetman BJ, Oates JA. Metabolism of thromboxane B₂ in man: identification of twenty urinary metabolites. J. Biol. Chem. 1981; 256: 8384-93.
• 35 Lawson J, Patrono C, Ciabattoni G, FitzGerald GA. Long-lived enzymatic metabolites of thromboxane B₂ in the human circulation. Anal Biochem 1986; 155: 198-205.
• 36 Ciabattoni G, Pugliese F, Davì G, Pierucci A, Simonetti BM, Patrono C. Fractional conversion of thromboxane B₂ to urinary 11-dehydro-TXB₂ in man. Biochim Biophys Acta 1989; 992: 66-70.
• 37 Hamberg M, Svensson J, Samuelsson B. Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides. Proc Natl Acad Sci USA 1975; 72: 2994-8.
• 38 Bhagwat SS, Hamann PR, Still WL, Bunting S, Fitzpatrick FA. Synthesis and structure of the platelet aggregation factor thromboxane A₂ . Nature 1985; 315: 511-3.
• 39 Patrignani P, Morton H, Cirino M, Lord A, Charette L, Gillard J, Rokach J, Patrono C. Fractional conversion of thromboxane A₂ and B₂ to urinary 2,3-dinor-thromboxane B₂ and 11-dehydro-thromboxane B₂ in the cynomolgus monkey. Biochim Biophys Acta 1989; 992: 71-7.
• 40 Patrono C, Davi G, Ciabattoni G. Thromboxane biosynthesis and metabolism in relation to cardiovascular risk factors. Trends Cardiovasc Med 1992; 2: 15-20.
• 41 Sala A, Voelkel N, Maclouf J, Murphy RC. Leukotriene E₄ elimination and metabolism in normal human subjects. J Biol Chem 1990; 265: 21771-8.
• 42 Maclouf J, Antoine A, De Caterina R, Sicari R, Murphy RC, Patrignani P, Loizzo S, Patrono C. Entry rate and metabolism of leukotriene C₄ into vascular compartment in healthy subjects. Am J Physiol 1992; 263: H244-H9.
• 43 van der Ouderaa FJ, Buytenhec M, Nugteren DH, van Dorp DA. Purification and characterisation of prostaglandin endoperoxide synthetase from sheep vesicular glands. Biochim Biophys Acta 1977; 487: 315-31.
• 44 Funk CD, Funk LB, Kennedy ME, Pong AS, FitzGerald GA. Human platelet/erythroleukemia cell prostaglandin G/H synthase: cDNA cloning, expression and gene chromosomal assignment. FASEB J 1991; 5: 2304-12.
• 45 Kujubu DA, Fletcher BS, Varnum BC, Lim RW, Herschman HR. TIS 10, a phorbol ester tumor promotor inducible mRNA from Swiss 3T3 cells encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem 1991; 266: 12866-72.
• 46 Xie W, Chipman JG, Robertson DL, Erikson RL, Simmons DL. Expression of a mitogen- responsive gene encoding prostaglandin G synthase is regulated by mRNA splicing. Proc Natl Acad Sci USA 1991; 88: 2692-6.
• 47 Jones DA, Carlton DP, Mc Intyre TM, Zimmerman GA, Prescott SM. Molecular cloning of human prostaglandin endoperoxide synthase type II and demonstration of expression in response to cytokines. J Biol Chem 1993; 268: 9049-54.
• 48 Smith WL, De Witt DL. Prostaglandin endoperoxide H synthases-1 and -2. Adv Immunol 1996; 62: 167-215.
• 49 Habib A, Créminon C, Frobert Y, Grassi J, Pradelles P, Maclouf J. Demonstration of an inducible cyclooxygenase in human endothelial cells using antibodies raised against the C-terminal region of the cyclooxygenase-2. J Biol Chem 1993; 268: 23448-54.
• 50 Laneuville O, Breuer DK, Xu N, Huang ZH, Gage DA, Watson JT, Lagarde M, De Witt DL, Smith WL. Fatty acid substrate specificities of human prostaglandin endoperoxide H synthases-1 and -2. Formation of 12-hydroxy-(9Z, 13E/Z, 15Z)-Octadecatrienoic acids from δ-linolenic acid. J Biol Chem 1995; 270: 19330-6.
• 51 Luong C, Miller A, Barnett J, Chow J, Ramesha C, Browner MF. Flexibility of the NSAID binding site in the structure of human cyclooxygenase-2. Nature Structural Biol 1996; 3: 927-33.
• 52 Kurumbail Stevens AM, Gierse JK, McDonald JJ, Stegeman RA, Pak JY, Gildehaus D, Miyashiro JM, Penning TD, Seibert K, Isakson PC, Stallings WC. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature 1996; 384: 644-8.
• 53 Otto JC, DeWitt DL, and Smith WL. N-glycosylation of prostaglandin endoperoxide synthases-1 and -2 and their orientation in the endoplasmic reticulum. J Biol Chem 1993; 268: 18234-42.
• 54 Picot D, Garavito RM. Prostaglandin H synthase: implications for membrane structure. FEBS Lett 1994; 346: 21-5.
• 55 Picot D, Loll PJ, Garavito M. The X-ray crystal structure of the membrane protein prostaglandin H₂ synthase-1. Nature 1994; 367: 243-9.
• 56 Morita I, Schindler M, Rigier MK, Otto JC, Hori T, De Witt DL, Smith WL. Different intracellular locations for prostaglandin endoperoxide H synthases-1 and -2. J Biol Chem 1995; 270: 10902-8.
• 57 Herschman HR. Prostaglandin synthase 2. Biochim Biophys Acta 1996; 1299: 125-40.
• 58 Asano K, Lilly CM, Drazen JM. Prostaglandin G/H synthase-2 is the constitutive and dominant isoform in cultured human lung epithelial cells. Am J Physiol 1996; 271: L126-31.
• 59 Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature New Biol 1971; 231: 232-5.
• 60 Smith WL, Lands WE. Stimulation and blockade of prostaglandin biosyn-thesis. J Biol Chem 1971; 246: 6700-2.
• 61 Roth GJ, Majerus PW. The mechanism of the effect of aspirin on human platelets. I. Acetylation of a particulate protein fraction. J Clin Invest 1975; 56: 624-32.
• 62 Lecomte M, Laneuville O, Ji C, De Witt DL, Smith WL. Acetylation of human prostaglandin endoperoxide synthase-2 (cyclooxygenase-2) by aspirin. J Biol Chem 1994; 269: 13207-15.
• 63 Claria J, Serhan C. Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cells-leukocyte interactions. Proc Natl Acad Sci USA 1995; 92: 9475-9.
• 64 Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest 1982; 69: 1366-72.
• 65 Loll PJ, Picot D, Garavito RM. The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H₂ synthase. Nature Structural Biol 1995; 2: 637-43.
• 66 Quellet M, Percival MD. Effect of inhibitor time-dependency on selectivity towards cyclooxygenase isoforms. Biochem J 1995; 306: 247-51.
• 67 Patrignani P, Panara MR, Greco A, Fusco O, Natoli C, Iacobelli S, Cipol-lone F, Ganci A, Créminon C, Maclouf J, Patrono C. Biochemical and pharmacological characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthases. J Pharmac Exp Ther 1994; 271: 1705-12.
• 68 Panara MR, Greco A, Santini G, Sciulli MG, Rotonda MT, Padovano R, di Giamberardino M. et al. Effects of the novel anti-inflammatory compounds, N-[2-(cyclohexyloxy)-4-nitrophenyl] methanesulphonamide (NS-398) and 5-methanesulphonamido-6-(2,4-difluorothio-phenyl)-1-indanone (L-745,337), on the cyclo-oxygenase activity of human blood prostaglandin endoperoxide synthases. Br J Pharmac 1995; 116: 2429-34.
• 69 Morrow JD, Hill KE, Burk RF, Nammour TM, Badr KF, Roberts II LJ. A series of prostaglandin F₂-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism. Proc Natl Acad Sci USA 1990; 87: 9383-7.
• 70 Lynch SM, Morrow JD, Roberts LJ II, Frei B. Formation of non-cyclooxygenase-derived prostanoids (F2-isoprostanes) in plasma and low density lipoprotein exposed to oxidative stress in vitro. J Clin Invest 1994; 93: 998-1004.
• 71 Pratico D, FitzGerald GA. Generation of 8-epi-prostaglandin F_2α by human monocytes. Discriminate production by reactive oxygen species and prostaglandin endoperoxide synthase-2. J Biol Chem 1996; 271: 8919-24.
• 72 Beaudeux JL, Césarini ML, Gardès-Albert M, Maclouf J, Esposito B, Peynet J, Tedgui A. Native and gamma radiolysis-oxidized lipoprotein(a) increase the adhesiveness of rabbit aoric endothelial cells. Atheroscleros 1997; 132: 29-35.
• 73 Pratico D, Iuliano L, Spagnoli L, Mauriello A, Maclouf J, Violi F, FitzGerald GA. Monocytes in human atherosclerotic plaque contain high levels of 8-epi PGF_2α: an index of oxidative stress in vivo . J Clin Invest 1997; 100: 2028-34.
• 74 Pratico D, Lawson JA, FitzGerald GA. Cyclooxygenase-dependent formation of the isoprostane, 8-epi prostaglandin F_2α . J Biol Chem 1995; 270: 9800-7.
• 75 Patrignani P, Santini G, Panara MR, Sciulli MG, Greco A, Rotondo MT, di Giamberardino M, Maclouf J, Ciabattoni G, Patrono C. Induction of prostaglandin endoperoxide synthase-2 in human monocytes associated with cyclooxygenase-dependent F₂-isoprostane formation. Br J Pharmacol 1996; 118: 1285-93.
• 76 Wang Z, Ciabattoni G, Créminon C, Lawson J, FitzGerald GA, Patrono C, Maclouf J. Immunological characterization of urinary 8-epi-prostaglandin F_2α excretion in man. J Pharm Exp Therapeut 1995; 275: 94-100.
• 77 Pratico D, Smyth EM, Violi F, FitzGerald GA. Local amplification of platelet function by 8-epi-prostaglandin F_2α is not mediated by thromboxane receptor isoforms. J Biol Chem 1996; 271: 14916-24.
• 78 Andrioli G, Lechi C, Fornasiero S, Gaino S, Ortolani R, Zuliani V, Tommasoli R, Lechi A, Minuz P. The F2-isoprostane 8-epi-PGF_2α increases platelet adhesion and the expression of adhesion molecule. Thromb Haemost 1997; Suppl PS2728 (Abstract).
• 79 Morrow J, Frei B, Longmire AW, Gaziano JM, Lynch SM, Shyr Y, Strauss WE, Oates JA, Roberts II LJ. Increase in circulating products of lipid peroxidation (F₂-isoprostanes) in smokers. N Engl J Med 1995; 332: 1198-203.
• 80 Gopaul NK, Änggard EE, Mallet AI, Betteridge DJ, Wolff C, NouroozZadeh J. Plasma 8-epi-PGF_2α levels are elevated in individuals with non-insulin dependent diabetes mellitus. FEBS Letters 1995; 368: 225-9.
• 81 Davi G, Alessandrini P, Mezzetti A, Minotti G, Bucciarelli T, Costantini F, Cipollone F, Bon G, Ciabattoni G, Patrono C. In vivo formation of 8-epi-PGF_2α is increased in hypercholesterolemia. Arterioscler Tromb Vasc Biol 1997; 17: 3230-5.
• 82 Marcus AJ. Thrombosis and inflammation as multicellular processes: pathophysiologic significance of transcellular metabolism. Blood 1990; 76: 1903-7.
• 83 Ross R. The pathogenesis of atherosclerosis, a perspective for the 1990s. Nature 1993; 362: 801-9.
• 84 Marcus AJ, and Hajjar DP. Vascular transcellular signaling. J Lipid Res 1993; 34: 2017-31.
• 85 Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion. Cell 1992; 69: 11-25.
• 86 Sporn MB, Roberts AB. Autocrine secretion-10 years later. Ann Int Med 1992; 117: 408-14.
• 87 Bunting S, Gryglewski R, Moncada S, Vane JR. Arterial walls generate from prostaglandin endoperoxides a substance (prostaglandin X) which relaxes strips of mesenteric and coeliac arteries and inhibits platelet aggregation. Prostaglandins 1976; 12: 897-913.
• 88 Marcus AJ, Weksler BB, Jaffe EA, Broekman MJ. Synthesis of prostacyclin from platelet-derived endoperoxides by cultured human endothelial cells. J Clin Invest 1980; 66: 979-86.
• 89 Fitzpatrick FA, Liggett W, McGee J, Bunting S, Morton D, Samuelsson B. Metabolism of leukotriene A₄ by human erythrocyte: A novel cellular source of leukotriene B₄ . J Biol Chem 1984; 259: 11403-7.
• 90 McGee JE, Fitzpatrick FA. Erythrocyte-neutrophil interactions: Formation of leukotriene B₄ via transcellular biosynthesis. Proc Natl Acad Sci USA 1986; 83: 1349-53.
• 91 Feinmark SJ, Cannon PJ. Endothelial cells leukotriene C₄ synthesis results from intercellular transfer of leukotriene A₄ synthesized by polymorpho-nuclear leukocytes. J Biol Chem 1986; 261: 16466-72.
• 92 Claesson HE, Haeggström J. Human endothelial cells stimulate leuko triene synthesis and convert granulocyte-released leukotriene A₄ into leukotrienes B₄, C₄, D₄ and E₄ . Eur J Biochem 1988; 173: 93-100.
• 93 Maclouf J, Murphy RC, Henson PM. Transcellular sulfidopeptide leukotriene biosynthetic capacity of vascular cells. Blood 1989; 74: 703-7.
• 94 Maclouf J, Henson P, Murphy RC. Transcellular biosynthesis of sulfido-peptide leukotrienes during receptor-mediated stimulation of human neutrophil/platelet mixtures. Blood 1990; 76: 1838-44.
• 95 Feinmark SJ, Cannon PJ. Vascular smooth muscle cells leukotriene C₄ synthesis: requirement for transcellular leukotriene A₄ metabolism. Biochim Biophys Acta 1987; 922: 125-35.
• 96 Maclouf J, Murphy RC. Transcellular metabolism of neutrophil-derived leukotriene A₄ by human platelets. J Biol Chem 1988; 263: 174-81.
• 97 Edenius C, Heidvall K, Lindgren JE. Novel transcellular interaction: conversion of granulocyte-derived leukotriene A₄ to cysteinyl-containing leukotrienes by human platelets. Eur J Biochem 1988; 178: 81-6.
• 98 Habib A, Maclouf J. Comparison of leukotriene A₄ metabolism into leukotriene C₄ by human platelets and endothelial cells. Archives Biochem Biophys 1992; 298: 544-52.
• 99 Scoggan KA, Jakobsson P-J, Ford-Hutchinson AW. Production of leukotriene C₄ in different human tissues is attributable to distinct membrane bound biosynthetic enzymes. J Biol Chem 1997; 272: 10182-7.
• 100 Brady HR, Serhan CN. Adhesion promotes transcellular leukotriene bio-synthesis diring neutrophil-glomerular endothelial cell interactions: inhibition by antibodies against CD18 and L-selectin. Biochem Biophys Res Commun 1992; 186: 1307-14.
• 101 Edenius C, Haeggström J, Lindgren JA. Transcellular conversion of en dogenous arachidonic acid to lipoxins in mixed human platelet-granulocyte suspensions. Biochem Biophys Res Commun 1988; 157: 801-7. Erratum Biochem Biophys Res Commun 1989; 159: 370.
• 102 Romano M, Chen XS, Takahashi Y, Yamamoto S, Funk CD, Serhan CN. Lipoxin synthase activity of human platelet 12-lipoxygenase. Biochem J 1993; 296: 127-33.
• 103 Lucchesi BR, Mullane KM. Leukocytes and ischemia-induced myocardial injury. Annu Rev Pharmacol Toxicol 1986; 26: 201-24.
• 104 Friedman GD, Klatsky AL, Siegelaub AB. The leukocyte count as a predictor of myocardial infarction. N Engl J Med 1974; 290: 1275-8.
• 105 Noble B, Ken K, Taverne J, Dipirro J, VanLiew J, Dijkstra C, Janossy G, Poulter LW. Mononuclear cells in glomeruli and cytokines in urine reflect the severity of experimental proliferative immune-complex glomerulonephritis. Clin Exp Immunol 1990; 80: 281-7.
• 106 Brigham KL, Meyrick B. Interactions of granulocytes with the lungs. Circ Res 1984; 54: 62-70.
• 107 Hickman P, McCollum PT, Belch JF. Neutrophils may contribute to the morbidity and mortality of claudicants. Br J Surgery 1994; 81: 790-8.
• 108 Harlan JM. Leukocyte-endothelial interactions. Blood 1985; 65: 513-25.
• 109 Grimminger F, Kreusler B, Schneider U, Becker G, Seeger W. Influence of microvascular adherence on neutrophil leukotriene generation. Evidence for cooperative eicosanoid synthesis. J Immunol 1990; 144: 1866-72.
• 110 Grimminger F, Becker G, Seeger W. High yield enzymatic conversion of intravascular LTA₄ in blood free perfused lungs. J Immunol 1988; 141: 2431-6.
• 111 Palmentier R, Krump E, Rocheleau H, Laviolette M, Borgeat P. Dynamics of 5-LO product synthesis by human neutrophils and eosinophils in plasma and salt solution. Inflammation Res 1995; 44: S259.
• 112 Lam BK, Owen WF, Austen KF, Soberman RJ. The identification of a distinct export step following the biosynthesis of LTC₄ by human eosinophils. J Biol Chem 1989; 264: 12885-9.
• 113 NF Voelkel, J Czartolomna, J Simpson, RC Murphy.. FMLP causes eicosanoi-dependent vasoconstriction and edema in lungs from endotoxin-primed rats. Am Rev Respir Dis 1992; 145: 701-11.
• 114 Grimminger F, Kreusler B, Schneider U, Witzeleben EV, Walmrath D, Neppert J, Seeger W. Human leukoagglutininating antibody evokes cooperative leukotriene synthesis in pulmonary microvasculature; model of transfusion-related acute lung injury. Circ Res 1991; 68: 503-12.
• 115 Maugeri N, Evangelista V, Piccardoni P, Dell’Elba G, Celardo A, deGaetano G, Cerletti C. Transcellular metabolism of arachidonic acid: increased platelet thromboxane generation in the presence of activated polymorphonuclear leukocytes. Blood 1992; 80: 447-51.
• 116 Sala A, Bolla M, Zarini S, Muller-Peddinghaus R, Folco GC. Release of leukotriene A₄ vs. leukotriene B₄ from human polymorphonuclear leukocytes. J Biol Chem 1996; 271: 17944-8.
• 117 Chauncey JB, Simon RH, Peters-Golden M. Rat alveolar macrophages synthesize LTB₄ and 12-HETE from alveolar epithelial cell-derived arachidonic acid. Am Rev Respir Dis 1988; 138: 928-35.
• 118 Chavis C, Vachier I, Chanez P, Bousquet J, Godard P. 5(S),15(S)-dihydroxyeicosatetraenoic acid and lipoxin generation in human polymorpho-nuclear cells: dual specificity of 5-lipoxygenase towards endogenous and exogenous precursors. J Exp Med 1996; 183: 1633-43.
• 119 Forman MB, Virmani R, Puett DW. Mechanisms and therapy of myocar-dial reperfusion injury. Circulation 1990; 81: 69-78.
• 120 Fisher TC, Meiselmann HJ. PMN in ischemic vascular disease. Thromb Res 1994; 74: 21-34.
• 121 Sala A, Rossoni R, Buccellati C, Berti F, Folco G, Maclouf J. Formation of sulphidopeptide-leukotrienes by cell-cell interaction causes coronary vasoconstriction in isolated, cell-perfused heart of rabbit. Br J Pharmac 1993; 110: 1206-12.
• 122 Rossoni G, Sala A, Berti F, Testa T, Buccellati C, Molta C, Muller-Peddinghaus R, Maclouf J, Folco G. Myocardial protection by the leukotriene synthesis inhibitor BAY X1005: importance of transcellular biosynthesis of cysteinyl-leukotrienes. J Pharm Exp Ther 1996; 276: 335-41.
• 123 Evers AS, Murphree S, Saffitz JE, Jakschik BA, Needleman P. Effect of endogenously produced leukotrienes, thromboxane and prostaglandins on coronary vascular resistance in rabbit myocardial infarction. J Clin Invest 1985; 75: 992-9.
• 124 Sala A, Aliev GM, Rossoni G, Berti F, Buccellati C, Burnstock G, Folco G, Maclouf J. Morphological and functional changes of coronary vasculature caused by transcellular biosynthesis of sulfidopeptide leukotrienes in isolated heart of rabbit. Blood 1996; 87: 1824-32.
• 125 Semb AG, Ytrehus K, Vaage J, Myklebust R. Cardiac injury by activated PMN: effect of cyclooxygenase and lipoxygenase inhibition evaluated by electron microscopy morphometry. J Mol Cell Cardiol 1996; 28: 311-20.
• 126 Hirata M, Hayashi Y, Ushikubi F, Yokota Y, Kageyama R, Naganishi S, Narumiya S. Cloning and expression of cDNA for a human thromboxane A₂ receptor. Nature 1991; 349: 617-20.
• 127 Hirata T, Kakizuka F, Fuse I, Okuma M, Narumiya S. Arg⁶⁰ to leu mutation of the human thromboxane A₂ receptor in a dominantly inherited bleeding disorder. J Clin Invest 1994; 94: 1662-7.
• 128 Raychowdhury MK, Yukawa M, Collins LJ, McGrail SH, Kent C, Ware JA. Alternative splicing produces a divergent cytoplasmic tail in the human endothelial thromboxane A₂ receptor. J Biol Chem 1994; 269: 19256-61.
• 129 Hirata T, Ushikubi F, Kakizuka A, Okuma M. Narumiya.. Two thromboxane A₂ in human platelets. Opposite coupling to adenylyl cyclase with different sensitivity to Arg⁶⁰ to leu mutation. J Clin Invest 1996; 97: 949-56.
• 130 Takahara K, Murray R, FitzGerald GA, Fitzgerald DJ. The response to thromboxane A₂ analogues in human platelets. Discrimination of two binding sites linked to distinct effector systems. Proc Natl Acad Sci USA 1990; 265: 6836-44.
• 131 Habib A, Vezza R, Créminon C, Maclouf J, FitzGerald G. Rapid, agonist-dependent phosphorylation in vivo of human thromboxane receptor iso-forms. Minimal involvement of protein kinase C. J Biol Chem 1997; 272: 7191-200.
• 132 Boie Y, Rushmore TH, Darmon-Goodwin A, Grygorczyk R, Slipetz DM, Metters KM, Abramovitz M. Cloning and expression of a cDNA for the human prostanoid IP receptor. J Biol Chem 1994; 269: 12173-8.
• 133 Oida H, Namba T, Sugimoto Y, Ushikubi F, Ohishi H, Ichikawa A. Narumiya In situ hybridization studies of prostacyclin receptor mRNA expression in various organs. Br J Pharmacol 1995; 116: 2828-37.
• 134 Smyth EM, Nestor PV, FitzGerald GA. Agonist-dependent phsophorylation of an epitope-tagged human prostacyclin receptor. J Biol Chem 1996; 271: 33698-704.
• 135 Murata T, Ushikubi F, Matsuoka T, Hirata M, Yamasaki A, Sugimoto Y, Ichikawa A, Aze Y, Tanaka T, Yoshida N, Ueno A, Oh-Ishi S, Narumiya S. Altered pain perception and inflammatory response in mice lacking prostacyclin receptor. Nature 1997; 388: 678-82.
• 136 Murata T, Matsuoka T, Yoshida N, Hirata M, Ushikubi F, Narumiya S. Analysis of IP receptor-deficient mice. Keystone symposia, Lipid mediators: recent advances in molecular biology, understanding of regulation and pharmacology. 1997 (Abstract).
• 137 Ushikubi F, Hirata M, Narumiya S. Molecular biology of prostanoid receptors; an overview. J Lipid Mediators Cell Signalling 1995; 12: 343-59.
• 138 Bernard C. Tedgui A: Cytokine network and the vessel wall.. Insights into the septic shock pathogenesis. Eur Cytokine Netw 1992; 3: 19-33.
• 139 Di Rosa M, Ialenti A, Sautebin L. Interaction between nitric oxide and cyclooxygenase pathways. Prostaglandins Leukotrienes Ess Fatty Acids 1995; 54: 229-38.
• 140 Salvemini D, Seibert K, Masferrer JL, Misko TP, Currie MG, Needleman P. Endogenous nitric oxide enhances prostaglandin production in a model of renal inflammation. J Clin Invest 1994; 93: 1940-7.
• 141 Salvemini D, Misko TP, Masferrer JL, Seibert K, Currie MG, Needleman P. Nitric oxide activates cyclooxygenase enzymes. Proc Natl Acad Sci USA 1993; 90: 7240-4.
• 142 Davidge ST, Baker PN, McLaughlin MK, Roberts JM. Nitric oxide produced by endothelial cells increases production of eicosanoids through activation of prostaglandin H synthase. Circ Res 1995; 77: 274-83.
• 143 Tsai A, Wei C, Kulmacz RJ. Interaction between nitric oxide and prostaglandin H synthase. Arch Biochem Biophys 1994; 313: 367-72.
• 144 Habib A, Bernard Lebret M, Créminon C, Esposito B, Tedgui A, Maclouf J. Regulation of the expression of cyclooxygenase-2 by nitric oxide in rat peritoneal macrophages. J Immunol 1997; 158: 3845-51.
• 145 Sautebin L, Ialenti A, Ianaro A, Di Rosa M. Modulation by nitric oxide of prostaglandin biosynthesis in the rat. Br J Pharmacol 1995; 114: 323-8.
• 146 Stadler J, Harbrecht BG, Di Silvio M, Curran RD, Jordan ML, Simmons RL, Billiar TR. Endogenous nitric oxide inhibits the synthesis of cyclooxygenase products and interleukin-6 by rat Kupffer cells. J Leukoc Biol 1993; 53: 465-72.
• 147 Henrion D, Dechaux E, Dowell FJ, Maclouf J, Samuel J-L, Levy BI, Michel J-B. Alteration of flow-induced dilation in mesenteric resistance arteries of L-NAME treated rats is partially associated to induction of cyclooxygenase-2. Brit J Pharmacol 1997; 121: 83-90.
• 148 Gaillard T, Mülsch A, Klein H, Deckerv K. Regulation by prostaglandin E₂ of cytokine-elicited nitric oxide synthesis in rat liver macrophages. Biol Chem Hoppe-Seyler 1992; 373: 897-902.
• 149 Pang L, Hoult JRS. Induction of cyclooxygenase and nitric oxide synthase in endotoxin-activated J774 macrophages is differentially regulated by indomethacin: enhanced cyclooxygenase-2 protein expression but reduction of inducible nitric oxide synthase. Eur J Pharmacol 1996; 317: 151-5.
• 150 Thun MJ, Namboodiri MM, Heath CW. Aspirin use and reduced risk of fatal colon cancer. N Engl J Med 1991; 325: 1593-6.
• 151 Thun MJ. Aspirin, NSAIDs, and digestive tract cancers. Cancer Metastas Rev 1994; 13: 269-77.
• 152 Levy G. Prostaglandin H synthases, non-steroidal anti-inflammatory drugs, and colon cancer. FASEB J 1997; 11: 234-47.
• 153 Rimarachin JA, Jacobson JA, Szabo P, Maclouf J, Créminon C, Weksler BB. Regulation of cyclooxygenase-2 expression in aortic smooth muscle cells. Arterioscleros Thrombos 1994; 14: 1021-31.
• 154 Tsujii M, DuBois RN. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase-2. Cell 1995; 83: 495-501.
• 155 Langenbach R, Morham SG, Tiano HF, Loftin CD, Ghanayem BI, Chulada PC, Malher JF, Lee CA, Goulding EH, Kluckman KD, Kim HS, Smithies O. Prostaglandin synthase-1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration. Cell 1995; 83: 483-92.
• 156 Morham SG, Langenbach R, Loftin CD, Tiano HF, Vouloumanos N, Jennette JC, Malher JF, Kluckman KD, Ledford A, Lee CA, Smithies O. Prostaglandin synthase-2 gene disruption causes severe renal pathology in the mouse. Cell 1995; 83: 473-82.
• 157 Prescott SM, White RL. Self-promotion? Intimate connection between APC and prostaglandin H synthase-2. Cell 1996; 87: 783-6.
• 158 Oshima M, Dinchuk JE, Kargman SL, Oshima H, Hancock B, Kwong E, Trzaskos JM, Evans JF, Taketo MM. Suppression of intestinal polyposis in Apc^Δ716 knockout mice by inhibition of cyclooxygenase-2 (COX-2). Cell 1996; 87: 803-9.
• 159 Ballif BA, Mincek NV, Barratt JT, Wilson ML, Simmons DL. Interaction of cyclooxygenases with an apoptosis- and autoimmunity-associated protein. Proc Natl Acad Sci USA 1996; 93: 5544-9.
• 160 Karim S, Habib A, Lévy-Toledano S, Maclouf J. Cyclooxygenases-1 and-2 of endothelial cells utilize exogenous or endogenous arachidonic acid for transcellular production of thromboxane. J Biol Chem 1996; 271: 12042-8.
• 161 Barry OP, Pratico D, Lawson JA, FitzGerald GA. Transcellular activation of platelets and endothelial cells by bioactive lipids in platelet microparticles. J Clin Invest 1997; 99: 2118-27.
• 162 FitzGerald GA, Smith B, Pedersen AK, Brash AR. Increased prostacyclin biosynthesis in patients with severe atherosclerosis and platelet activation. N Engl J Med 1984; 310: 1065-8.
• 163 Fitzgerald DJ, Roy L, Catella F, FitzGerald GA. Platelet activation in unstable coronary disease. N Engl J Med 1986; 315: 983-9.
• 164 Vejar M, Fragasso G, Hackett D, Lipkin DP, Maseri A, Born GVR, Ciabattoni G, Patrono C. Dissociation of platelet activation and spontaneous myocardial ischemia in unstable angina. Thromb Haemost 1990; 63: 163-8.
• 165 Cipollone F, Patrignani P, Greco A, Panara MR, Padovano R, Cuccurullo F, Patrono C. et al. Differential suppression of thromboxane biosynthesis by indobufen and aspirin in patients with unstable angina. Circulation 1997; 96: 1109-16.
• 166 Higgs GA, Moncada S, Vane JR. Prostaglandin I₂ reduces the number of “slow moving” leukocytes in hamster cheek pouch venules. J Physiol 1978; 280: 55-6.
• 167 Erlansson M, Bergqvist D, Person NH, Svensjo E. Modification of postischemic increase of PMN adhesion and vascular permeability in the hamster by Iloprost. Prostaglandins 1991; 41: 157-68.
• 168 Simpson PJ, Mickelson J, Fantone JC, Gallagher KP, Lucchesi BR. Iloprost inhibits PMN function in vitro and in vivo and limits experimental infarct size in canine heart. Circ Res 1987; 60: 666-73.
• 169 Rossoni G, Sala A, Buccellati C, Maclouf J, Folco G, Berti F. Prostacyclin prevents polymorphonuclear leukocyte-dependent coronary ischemia due to transcellular biosynthesis of sulphido-peptide leukotrienes in perfused heart of rabbit. J Cardiovasc Pharmacol 1996; 27: 680-5.
• 170 Buccellati C, Rossoni G, Bonazzi A, Berti F, Maclouf J, Folco G, Sala A. Nitric oxide modulation of transcellular biosynthesis of Cys-leukotrienes in rabbit leukocyte-perfused heart. Br J Pharmacol 1997; 120: 1128-34.
• 171 Zoldhelyi P, McNatt J, Xu X-M, Loose-Mitchell D, Meidell RS, Clubb Jr FJ, Buja M, Willerson JT, Wu KK. Prevention of arterial thrombosis by adenovirus-mediated transfer of cyclooxygenase gene. Circulation 1996; 93: 10-7.
• 172 Shoonjans K, Staels B, Auwerx J. The peroxisome activated receptors (PPARs) and their effects on lipid metabolism and adipocyte differentiation. Biochim Biophys Acta 1996; 1302: 93-109.
• 173 Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM. 15-deoxy Δ^12,14-prostaglandin J₂ is a ligand for the adipocyte determination factor. PPARγ Cell 1995; 83: 803-12.
• 174 Smith WL, DeWitt D. Do they still have headaches?. Cell 1995; 83: 345-8.
• 175 Catalioto RM, Gaillard D, Maclouf J, Ailhaud G, Négrel R. Autocrine control of adipose cell differenciation by prostacyclin and PGF_2α . Biochim Biophys Acta 1991; 1091: 364-9.
• 176 Hertz R, Berman I, Keppler D, Bar-Tana J. Activation of gene transcription by prostacyclin analogues is mediated by the peroxisome-proliferators-activated receptor (PPAR). Eur J Biochem 1996; 235: 242-7.
• 177 Aubert J, Ailhaud G, Négrel R. Evidence for a novel regulatory pathway activated by (carba)prostacyclin in preadipose and adipose cells. FEBS Letters 1996; 397: 117-21.
• 178 Yu K, Bayona W, Kallen CB, Harding HP, Ravera CP, McMahon G, Brown M, Lazar MA. Differential activation of peroxisome proliferator-activated receptors by eicosanoids. J Biol Chem 1996; 270: 23975-83.
• 179 Devchand PR, Keller H, Peters JM, Vazquez, Gonzalez FJ, Wahli W. The PPARα-leukotriene B₄ pathway to inflammation control. Nature 1996; 384: 39-43.
• 180 Forman BM, Chen J, Evans RM. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors δ and γ. Proc Natl Acad Sci USA 1997; 94: 4312-7.
• 181 Ledwith BJ, Pauley CJ, Wagner LK, Rokos CL, Alberts DW, Manam S. Induction of cyclooxygenase-2 expression by peroxisome proliferators and non-tetradecaoylphorbol 12,13-myristate-type tumor promoters in immortalized mouse liver cells. J Biol Chem 1997; 272: 3707-14.