Regulation of Eicosanoid Biosynthesis in Endothelial Cells: Critical Role of De Novo Synthesis of Prostaglandin Endoperoxide Synthase

  • Kenneth Kun-Yu Wu
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 281)


Prostaglandins are important autacoids participating in a myriad of physiologic and pathophysiologic processes. Biosynthesis of prostaglandins and eicosanoids is regulated at several enzymatic steps (1). As shown in Fig. 1, liberation of arachidonic acid from membrane phispholipids upon cell activation is catalyzed by phospholipases. This is a rate limiting step. Once arachidonic acid is liberated, it is metabolized via the cyclooxygenase and lipoxygenase pathways. The enzyme that is responsible for catalysis of arachidonic acid into endoperoxides is prostaglandin endoperoxide synthase (prostaglandin G/H synthase, prostaglandin H synthase or cyclooxygenase). This molecule possesses two enzymic activities: cyclooxygenase which catalyzes the oxygenation of arachidonic acid into prostaglandin G2 (PGG2) and peroxidase converting PGG2 into PGH2 (2). Prostaglandin H synthase is upregulated by peroxides including PGG2 but once PGG2 is converted to PGH2, oxygen radicals that are generated appear to cause irreversible inactivation of the cyclooxygenase activity (3-5). This leads to limited synthesis of PGH2. PGH2 is the common precursor for prostacyclin (PGI2), PGE2, PGF, PGD2 and thromboxane A2 (TXA2). With compromised PGH2 synthesis, production of these biologically active metabolites is consequently self-limited. This enzymatic step, hence, plays a central role in controlling eicosanoid biosynthesis.


Arachidonic Acid Phorbol Ester Arachidonic Acid Metabolism Prostaglandin Biosynthesis Cyclooxygenase Activity 
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  1. 1.
    W. E. M. Lands, The biosynthesis and metabolism of prostaglandins, Ann. Rev. Physiol., 41:633–652 (1979).CrossRefGoogle Scholar
  2. 2.
    S. Ohki, N. Ogino, S. Yamamoto, and O. Hayaishi, Prostaglandin hydroperoxidase an integral part of prostaglandin endoperoxide synthetase from bovine vascular gland microsomes, J. Biol. Chem., 254:829–836 (1979).PubMedGoogle Scholar
  3. 3.
    W. L. Smith and W. E. M. Lands, Oxygenation of polyunsaturated fatty acids during prostaglandin biosynthesis by sheep vesicular gland, Biochemistry, 11:3276–3285 (1972).PubMedCrossRefGoogle Scholar
  4. 4.
    R. W. Egan, J. Paxton, and F. A. Kuehl, Mecahnism for irreversible self-deactivation of prostaglandin synthetase, J. Biol. Chem., 251:7325–7335 (1976).Google Scholar
  5. 5.
    M. E. Hemler and W. E. M. Lands, Evidence for a peroxide-initiated free radical mechanism of prostaglandin biosynthesis, J. Biol. Chem., 255:6253–6261 (1980).PubMedGoogle Scholar
  6. 6.
    R. S. Kent, S. L. Diedrich, and J. Whorton, Regulation of vascular prostaglandin synthesis by metabolites of arachidonic acid in perfused rabbit aorta, J. Clin. Invest.,72:455–465 (1983).PubMedCrossRefGoogle Scholar
  7. 7.
    T. M. McIntire, K. S. Zimmerman, and S. M. Prescott, Cultured endothelial cells synthesize both platelet-activating factor and prostacyclin response to histamine, bradykinin, and adenosine triphosphate, J. Clin. Invest., 76:271–280 (1985).CrossRefGoogle Scholar
  8. 8.
    V. Rossi, G. Breviario, P. Ghezzi, E. Dejana, and A. Mantovani, Prostacyclin synthesis induced in vascular cells by interleukin-1, Science, 229:174–176 (1985).PubMedCrossRefGoogle Scholar
  9. 9.
    R. R. Schleef, M. P. Bevilacqua, M. Sawdey, M. A. Gimbrone, and D. J. Loskutoff, J. Biol. Chem., 263:5797–5803 (1988).PubMedGoogle Scholar
  10. 10.
    P. J. Whiteley and P. Needleman, Mecahnism of enhanced fibroblast arachidonic acid metabolism by mononuclear cells, J. Clin. Invest., 74:2249–2253 (1984).PubMedCrossRefGoogle Scholar
  11. 11.
    C. R. Albrightson, N. L. Baenziger, and P. Needleman, Exaggerated human vascular cell prostaglandin biosynthesis mediated by monocytes: Role of monokines and interleukin 1, J. Immunol., 135:1872–1877 (1985).PubMedGoogle Scholar
  12. 12.
    M. Hemler and W. E. M. Lands, Purification of the cyclooxygenase that forms Prostaglandins, J. Biol. Chem., 251:5575–5579 (1976).PubMedGoogle Scholar
  13. 13.
    T. Miyamoto, N. Ogino. S. Yamamoto, and O. Hayaishi, Purification of prostaglandin endoperoxide synthetase from bovine vesicular gland microsomes, J. Biol. Chem., 251:2629–2636 (1976).PubMedGoogle Scholar
  14. 14.
    F. J. Van der Ouderaa, M. Buytenhek, D. H. Nugteven, and D. A. Van Dorp, Purification and characterization of prostaglandin endoperoxide synthetase from sheep vesicular glands, Biochim. Biophys. Acta, 487:315–331 (1977).PubMedCrossRefGoogle Scholar
  15. 15.
    D. L. DeWitt and W. L. Smith, Primary structure of prostaglandin G/H synthase from sheep vesicular gland determined from complementary DNA sequence, Proc. Natl. Acad. Sci. (USA), 85:1412–1416 (1988).CrossRefGoogle Scholar
  16. 16.
    J. P. Merlie, D. Fagan, J. Mudd, and P. Needleman, Isolation and characterization of the complementary DNA for sheep seminal vesicle prostaglandin endoperoxide synthase, J. Biol. Chem., 263:3550–3553 (1988).PubMedGoogle Scholar
  17. 17.
    G. J. Roth, N. Stanford, and P. W. Majerus, Acetylation of prostaglandin synthase by aspirin, Proc. Natl. Acad. Sci. (USA), 72:3073–3076 (1975).CrossRefGoogle Scholar
  18. 18.
    R. J. Flower, Drugs which inhibit prostaglandin biosynthesis, Pharmacol. Reviews, 26:33–67 (1974).Google Scholar
  19. 19.
    J. W. Burch, N. L. Baenziger, N. Stanford, and P. W. Majerus, Sensitivity of fatty acid cyclooxygenase from human aorta to acetylation by aspirin, Proc. Natl. Acad. Sci. (USA), 75:5181–5184 (1978).CrossRefGoogle Scholar
  20. 20.
    J. M. Fagan and A. L. Goldberg, Inhibitors of protein and RNA synthesis cause a rapid block in prostaglandin production at the prostaglandin synthase step, Proc.Natl. Acad. Sci. (USA), 83:2771–2775 (1986).CrossRefGoogle Scholar
  21. 21.
    Y.-N. Chen, M. J. Bienkowki, and L. J. Marnett, Controlled tryptic digestion of prostaglandin H synthase, J. Biol. Chem., 262:16892–16899 (1987).PubMedGoogle Scholar
  22. 22.
    R. J. Kulmacz and K. K. Wu, Topographic studies of microsomal and pure prostaglandin H synthase, Arch. Biochem. Biophys., 268: 502–515 (1989).PubMedCrossRefGoogle Scholar
  23. 23.
    K. Frasier-Scott, H. Hatzakis, D. Seong, C. M. Jones, and K. K. Wu, Influence of natural and recombinant IL-2 on endothelial cell arachidonate metabolism, J. Clin. Invest.,82:1877–1883 (1988).PubMedCrossRefGoogle Scholar
  24. 24.
    K. K. Wu, H. Hatzakis, S. S. Lo, D. C. Seong, and S. K. Sanduja, Stimulation of de novo synthesis of prostaglandin G/H synthase in human endothelial cells by phorbol ester, J. Biol. Chem., 263:19043–19047 (1988).PubMedGoogle Scholar
  25. 25.
    G. A. Beaudry, M. Waite, and L. W. Daniel, Regulation of arachidonic acid metabolism in Madin-Darby canine kidney cells: Stimulation of synthesis of the cyclooxygenase system by 12–0-tetradecanoly-phrobol-13-acetate, Arch. Biochem. Biophys.,239:242–247 (1985).PubMedCrossRefGoogle Scholar
  26. 26.
    A. Raz, A. Wyche, and P. Needleman, Temporal and pharmacological division of fibroblast cyclooxygenase expression into transcriptional and translational phases, Proc. Natl. Acad. Sci. (USA), 86:1657–1661 (1989).CrossRefGoogle Scholar
  27. 27.
    P. A. Needleman, A. Wyche, and A. Raz, Platelet and blood vessel arachidonate metabolism and interactions, J. Clin. Invest., 63:345–349 (1979).PubMedCrossRefGoogle Scholar
  28. 28.
    A. J. Marcus, B. B. Weksler, E. A. Jaffe, and M. J. Broekman, Synthesis of prostacyclin from platelet derived endoperoxides by cultured human endothelial cells, J. Clin. Invest.,66:979–986 (1980).PubMedCrossRefGoogle Scholar
  29. 29.
    K. K. Wu, A. C. Papp, C. E. Manner, and E. R. Hall, Interaction between lymphocytes and platelets in the synthesis of prostacyclin, J. Clin. Invest.,79:1601–1606 (1987).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1990

Authors and Affiliations

  • Kenneth Kun-Yu Wu
    • 1
  1. 1.Department of Internal Medicine and Vascular Disease Research CenterUniversity of Texas Medical School at HoustonHoustonUSA

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