Prostacyclin as an Anti-Atherosclerotic Hormone — A Hypothesis

  • Ryszard J. Gryglewski
Part of the NATO Advanced Study Institutes Series book series


Although many factors in pathogenesis of atherosclerosis still remain unknown, intravascular activation of blood platelets seems to play an important role in the development of this disease. The thrombogenic hypothesis of atherosclerosis (the so called “incrustation theory”) was proposed as early as in 1842 by Carl von Rokitansky (1), but Virchow’s “infiltration theory” prevailed and dominated the academic community for many years, owing greatly to Anichkov’s experimental demonstration (2) that atherosclerosis in rabbits could be induced by a diet high in lipids and cholesterol content. The yellow streaks of lipids which “infiltrated” the rabbit aorta could be seen with the naked eye.


Platelet Aggregation Arterial Wall Atheromatic Plaque Atherogenic Diet Rabbit Aorta 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    C. Von Rokitansky, Handbuch der Patologischen Anatomie, Bd. 4 1842, English translation by G. E. Day, Sydenham Society, London, 1852: 261.Google Scholar
  2. 2.
    N. Anitschkow, Uber Veranderungen der Kaninchen-Aorta bei experimenteller Cholesterinsteatose, Beitr. Anat. Allg. Path., 56: 379 (1913).Google Scholar
  3. 3.
    W. C. Roberts and V. J. Ferrans, The role of thrombosis in the etiology of atherosclerosis (a positive one) and in precipitating fatal ischemic heart disease (a negative one). In: “Current Cardiovascular Topics”,Vol.2., “Thrombosis, Platelets, Anticoagulation and Acetylsalicylic Acid”, E. Donoso and J. I. Haft, Georg Thieme Pub., Stuttgart, (1976).Google Scholar
  4. 4.
    J. I. Haft, Platelets, coronary artery disease and stress, In: “Current Cardiovascular Topics, Vol. II, Thrombosis, Platelets, Anti-Coagulation and Acetylsalicylic Acid”, E. Donoso and J. I. Haft, Georg Thieme, Stuttgart 97 (1976).Google Scholar
  5. 5.
    J. F. Mustard and M. A. Packham, Platelet thrombosis and drugs, Drugs, 9: 19 (1975).PubMedCrossRefGoogle Scholar
  6. 6.
    H. R. Baumgartner, Platelet interaction with vascular structures. Thromb. Diath. Haemorrh. Suppl., 43: 161 (1971).Google Scholar
  7. 7.
    S. Niewiarowski, F. Regoeczi, G. J. Stewart, A. Senyi and J. F. Mustard, Platelet interaction with polymerizing fibrin. J. Clin. Invest., 51: 685 (1972).PubMedCrossRefGoogle Scholar
  8. 8.
    R. Ross, J. Glomset, R. Kariya and L. Harker, A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscle sells in vitro. Proc. Natl. Acad. Sci. USA, 71: 1207 (1974).PubMedCrossRefGoogle Scholar
  9. 9.
    H. N. Antoniades, C. D. Scher and C. D. Stiles, Purification of human platelet-derived growth factor, Proc. Natl. Acad. Sci. USA, 76: 1809 (1979).PubMedCrossRefGoogle Scholar
  10. 10.
    A. W. Clowes and M. J. Karnowsky, Failure of certain anti-platelet drugs to affect myointimal thickening following arterial endothelial injury in the rat. Lab. Invest., 36: 452 (1977).PubMedGoogle Scholar
  11. 11.
    L. A. Harker, S. J. Slichter, R. Scott and R. Ross, Homocystinemia—vascular injury and arterial thrombosis. N. Engl. J. Med., 291: 537 (1974).PubMedCrossRefGoogle Scholar
  12. 12.
    R. Ross and J. A. Flomset, Atherosclerosis and the arterial smooth muscle cell. Science, 180: 1332 (1973).PubMedCrossRefGoogle Scholar
  13. 13.
    R. Ross and J. A. Glomset, The pathogenesis of atherosclerosis (two parts). New Engl. J. Med., 295:369 and 420 (1976).Google Scholar
  14. 14.
    R. J. Gryglewski, S. Bunting, S. Moncada, R. J. Flower and J. R. Vane, Arterial walls are protected against deposition of platelet thrombi by a substance (Prostaglandin X) which they make from prostaglandin endoperoxide. Prostaglandins, 12: 685 (1976).PubMedGoogle Scholar
  15. 15.
    S. Moncada, R. J. Gryglewski, S. Bunting and J. R. Vane, An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature, 263: 663 (1976).PubMedCrossRefGoogle Scholar
  16. 16.
    R. J. Gryglewski, R. Korbut and A. Ocetkiewicz; Generation of prostacyclin by lungs in vivo and its release into the arterial circulation. Nature, 273: 765 (1978).PubMedCrossRefGoogle Scholar
  17. 17.
    S. Moncada, R. Korbut, S. Bunting and J. R. Vane, Prostacyclin is a circulating hormone. Nature, 273: 767 (1978).PubMedCrossRefGoogle Scholar
  18. 18.
    R. J. Gryglewski, R. Korbut and J. Splawinski, Endogenous mechanisms which regulate prostacyclin release. Haemostasis in press.Google Scholar
  19. 19.
    R. J. Shebuski and J. W. Aiken, Angiotensin II induced renal prostacyclin release suppresses platelet aggregation in the anaesthetized dog. Abstracts of IVth International Prostaglandin Conference, Washingotn, D.C. May 27–31, 1979.Google Scholar
  20. 20.
    K. M. Mullane, S. Moncada and J. R. Vane, Prostacyclin release induced by bradykinin may contribute to the anti-hypertensive action of angiotensin converting enzyme inhibitors. Abstracts of IVth International Prostaglandin Conference, Washington, D.C. 27–31 May, 1979.Google Scholar
  21. 21.
    R. R. Gorman, S. Bunting and 0. V. Miller, Modulation of human platelet adenylate cyclase by prostacyclin (PGX), Prostaglandins, 13: 377 (1977).PubMedGoogle Scholar
  22. 22.
    R. J. Gryglewski, A. Dembinska-Kiec, A Chytkowski and T. Gryglewska, Prostacyclin and thromboxane A2 biosynthesis capacities of heart, arteries and platelets at various stages of experimental atherosclerosis in rabbits. Atherosclerosis, 31: 385 (1978).PubMedCrossRefGoogle Scholar
  23. 23.
    J. D. Wojcik, D. L. Vanhorn and A. J. Weber, Mechanism whereby platelets support endothelium. Transfusion, 9: 324 (1969).PubMedCrossRefGoogle Scholar
  24. 24.
    M. A. Gimbrone, R. H. Aster and R. S. Cotran, Preservation of vascular integrity in organs perfused in vitro with platelet-rich medium. Nature (London), 222: 33 (1969).CrossRefGoogle Scholar
  25. 25.
    S. A. Johnson, Endothelial supporting function of platelets, In: “The Circulating Platelets”, S. A. Johnson, ed., Academic Press, New York (1971).Google Scholar
  26. 26.
    S. Moncada, R. J. Gryglewski, S. Bunting and J. R. Vane, A lipid peroxide inhibits the enzyme in blood vessel microsomes that generates from prostaglandin endoperoxides the substance (prostaglandin X) which prevents platelet aggregation. Prostaglandins, 12: 715 (1976).PubMedGoogle Scholar
  27. 27.
    S. Bunting, R. J. Gryglewski, S. Moncada and J. R. Vane, Arterial walls generate from prostaglandin endoperoxides a substance (Prostaglandin X) which relaxes strips of mesenteric and coeliac arteries and inhibits platelet aggregation. Prostaglandins, 12: 897 (1976).PubMedGoogle Scholar
  28. 28.
    R. L. Tansik, D. H. Namm and H. L. White, Synthesis of prostaglandin 6-keto PGF1 by cultured aortic smooth muscle cells and stimulation of its formation in a coupled system which platelet lysates. Prostaglandins, 15: 399 (1978).PubMedGoogle Scholar
  29. 29.
    G. Hornstra, E. Haddeman and J. A. Don, Some investigations into the role of prostacyclin in thromboregulation. Thromb. Res., 12: 367 (1978).PubMedCrossRefGoogle Scholar
  30. 30.
    P. P. K. Ho, R. G. Herrmann, R. D. Towner and C. P. Walters, Reversal of platelet aggregation by aortic microsomes. Biochem. Biophys. Res. Commun., 74: 514 (1977).PubMedCrossRefGoogle Scholar
  31. 31.
    N. Begent and G. V. R. Born, Growth rate in vivo of platelet thrombi, produced by ionophoresis of ADP as a function of mean blood flow velocity, Nature (London) 227: 926 (1970).CrossRefGoogle Scholar
  32. 32.
    E. Marcinkiewicz, L. Grodzinska and R. J. Gryglewski, Platelet aggregation and thromboxane A2 formation in cat platelet rich plasma. Pharmacol. Res. Commun., 10: 1 (1978).PubMedCrossRefGoogle Scholar
  33. 33.
    L. Grodzinska and E. Marcinkiewicz, The generation of TXA2 in human platelets rich plasma and its inhibition by nictindole and prostacyclin. Pharmacol. Res. Commun., 11: 133 (1979).PubMedCrossRefGoogle Scholar
  34. 34.
    J. A. Salmon, D. R. Smith, R. J. Flower, S. Moncada and J. R. Vane, Further studies on the enzymatic conversion of prostaglandin endoperoxide into prostacyclin in porcine aorta microsomes. Biochim. Biophys. Acta., 523: 250 (1978).PubMedCrossRefGoogle Scholar
  35. 35.
    T. H. Spaet and R. B. Erichson, The vascular wall in the pathogenesis of thrombosis. Thromb. Diath. Haemorrh. Suppl. 21:67 (1966) .Google Scholar
  36. 36.
    R. J. Gryglewski, R. Korbut and A. Ocetkiewicz, Deaggregatory action of prostacyclin in vivo and its enhancement by theophylline. Prostaglandins, 15: 637 (1978).PubMedGoogle Scholar
  37. 37.
    R. J. Gryglewski, R. Korbut and A. Ocetkiewicz, Reversal of platelet aggregation by prostacyclin. Pharmacol. Res. Commun. 10: 185 (1978).PubMedCrossRefGoogle Scholar
  38. 38.
    R. J. Gryglewski, Prostacyclin as a circulatory hormone. Biochem. Pharmacol. in press (1979).Google Scholar
  39. 39.
    K. E. Arfors, H. C. Hint, D. P. Dhall and N. A. Matheson, Counteraction of platelet activity at sites of laser-induced endothelial thrauma. Br. Med. J., 4: 430 (1968).PubMedCrossRefGoogle Scholar
  40. 40.
    A. J. Marcus, B. B. Weksler and E. A. Jaffe, Enzymatic conversion of prostaglandin endoperoxide H2 and arachidonic acid to prostacyclin by cultured human endothelial cells. J. Biol. Chem., 253: 7138 (1978).PubMedGoogle Scholar
  41. 41.
    A. Dembinska-Kiee, T. Gryglewska, A. Zmuda and R. J. Gryglewski, The generation of prostacyclin by arteries and by the coronary vascular bed is reduced in experimental atherosclerosis in rabbits. Prostaglandins, 14: 1025 (1977).Google Scholar
  42. 42.
    G. Masotti, G. Galanti, L. Poggesi, A. Curcio and G. G. Neri Sem eri, Early changes of the endothelial antithrombotic properties in cholesterol fed rabbits. III-decreased PGI2 production by aortic wall. Thrombos. Haemostas., 42:423 (1979) .Google Scholar
  43. 43.
    P. A. Berberian, V. A. Ziboh, S. L. Hsia, Prostaglandin E2 biosynthesis: changes in rabbit aorta and skin during experimental atherosclerosis. J. Lipid Res., 17: 46 (1976).PubMedGoogle Scholar
  44. 44.
    A. Zmuda, A. Dembinska-Kiee, A. Chytkowski and R. J. Gryglewski, Experimental atherosclerosis in rabbits: Platelet aggregability, thromboxane A2 generation and anti-aggregatory potency of prostacyclin. Prostaglandins, 14: 1035 (1977).PubMedGoogle Scholar
  45. 45.
    G. Cohen, Lipid peroxidation: detection in vivo and in vitro through the formation of saturated hydrocarbon gases. In: Ciba Foundation Symposium 65 “Oxygen Free Radicals and Tissue Damage”, Excerpta Medical, Amsterdam, Oxford,New York (1979).Google Scholar
  46. 46.
    J. Glavind, S. Hartman, J. Clemensen, K. E. Jessen and H. Dam, Studies on the role of lipid peroxides in human pathology. II. The presence of peroxidized lipids in the atherosclerotic aortas. Acta.Pathm.Microbiol. Scand., 30: 1 (1952).CrossRefGoogle Scholar
  47. 47.
    K. Fukuzumi, Lipids of atherosclerotic artery. The cause of atherosclerosis from the view point of fat chemistry. Fette. Seifen, Anstrichmittel, 11: 953 (1969).CrossRefGoogle Scholar
  48. 48.
    T. Hiramitsu, Y. Majima, Y. Hasegava, K. Hirata and K. Yaki, Lipidperoxide formation in the retina in ocular siderosis. Experientia, 32: 1324 (1976).PubMedCrossRefGoogle Scholar
  49. 49.
    W. S. Hartroft and E. A. Prta, Ceroid. Amer. J. Med. Sci., 250: 324 (1965).CrossRefGoogle Scholar
  50. 50.
    V. Angelo, M. Mysliwiec, M. B. Donati and G. Gaetano, Defective fibrinolytic and prostacyclin-like activity in human atheromateus plaques. Thrombos. Haemostas., 39: 535 (1978).Google Scholar
  51. 51.
    M. Mysliwiec, S. Villa, G. de Gaetano and M. B. Donati, Decreased plasminogen activator (PA) but normal prostacyclin (PGI2) activity in veins with experimental thrombosis. Thrombos. Haemostas., 42: 7 (1979).Google Scholar
  52. 52.
    P. D. Vinocour, H. M. Groves, E. Dejana, R. L. KinloughRathbone and F. J. Mustard, The effects of dietary fats in rabbits on platelet survival, platelet turnover, platelet density, PGI2 production and thrombus formation in response to an aortic indwelling cannula. Thrombos. Haemostas., 42: 423 (1979).Google Scholar
  53. 53.
    J. L. Weihrauch, C. A. Brignoli, J. N. Reeves and L. Iverson, Fatty acid composition of margarines, processed fats and oils. Food Technol., 1: 80 (1977).Google Scholar
  54. 54.
    S. Taura, M. Taura and F. A. Kummerow, Human arterio-and atherosclerosis; identical to that in 6 and 36 month old swine fed a corn soy diet free of cholesterol and saturated fat. Artery, 4: 100 (1978).Google Scholar
  55. 55.
    R. B. Wilson, N. S. Kula, P. M. Newberne and M. W. Conner, Vascular damage and lipid peroxidation in choline-deficient rats. Exper. Molecul. Path., 18: 357 (1973).CrossRefGoogle Scholar
  56. 56.
    A. Dembinska-Kieé, W. Ricker, P. S. Schönhöfer, Atherosclerosis decreases prostacyclin synthesis in rabbit lungs and kidneys. Prostaglandins in press (1979).Google Scholar
  57. 57.
    A. Dembinska-Kiee, W. Rucker, P. S. Schönhöfer, Effects of dipyridamole in vivo on ATP and cAMP content in platelets and arterial walls and on atherosclerotic plaque formation. Naunyn-Schmiedeberg’s Arch. Pharmacol., in press (1979).Google Scholar
  58. 58.
    A. Dembinska-Kieé, W. Rücker, P. S. Schönhöfer, Effects of dipyridamole in experimental atherosclerosis: Action of PGI2, platelet aggregation and atherosclerotic plaque formation. Atherosclerosis, in press (1979).Google Scholar
  59. 59.
    H. Sinzinger, P. Clopath and K. Silberbauer, Increased prostacyclin generation in minipig vascular tissue after atherogenic diet. Thrombos. Haemostas., 42: 424 (1979).Google Scholar
  60. 60.
    A. Szczeklik, R. J. Gryglewski, R. Nizankowski, J. Musial, R. Pieton and J. Mruk, Circulatory and anti-platelet effects of intravenous prostacyclin in healthy men. Pharmacol. Res. Commun., 10: 545 (1978).PubMedCrossRefGoogle Scholar
  61. 61.
    R. J. Gryglewski, A. Szczeklik and R. Nizankowski, Anti-platelet action of intravenous infusion of prostacyclin in man. Thrombos. Res., 13: 153 (1978).CrossRefGoogle Scholar
  62. 62.
    A. Szczeklik, R. Nizankowski, S. Skawinski, J. Szczeklik, P. Gluszko and R. J. Gryglewski, Successful therapy of advanced arteriosclerosis obliterans with prostacyclin. Lancet, 1: 1111 (1979).PubMedCrossRefGoogle Scholar
  63. 63.
    J. D. Coffman, Drug therapy; vasodilator drugs in peripheral vascular disease. New Engl. J. Med., 300: 713 (1979).PubMedCrossRefGoogle Scholar
  64. 64.
    A. G. Olsson and T. Jogestrand, Effects of prostaglandin El in peripheral vascular disease. In: International Conference on Atherosclerosis, Milan 1977, L. A. Carlson, R. Paoletti, Siroti and G. Weber, Raven Press, New York (1978) .Google Scholar
  65. 65.
    F. Numano, Progression and regression of atherosclerosis. Asian Med. J., 20: 625 (1977).Google Scholar
  66. 66.
    R. Ross, L. Harker, Hyperlipidemia and atherosclerosis. Science, 193: 1094 (1976).PubMedCrossRefGoogle Scholar
  67. 67.
    F. Numano, H. Maezawa, T. Shimamoto, K. Adachi, Changes of cyclic AMP and cyclic AMP phosphodiesterase in the progression and regression of experimental atherosclerosis. Ann. NY Acad. Sci., 275: 311 (1976).PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1981

Authors and Affiliations

  • Ryszard J. Gryglewski
    • 1
  1. 1.Department of PharmacologyCopernicus Academy of MedicineCracowPoland

Personalised recommendations