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Blood Radicals: Reactive Nitrogen Species, Reactive Oxygen Species, Transition Metal Ions, and the Vascular System

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Abstract

Free radicals, such as superoxide, hydroxyl and nitric oxide, and other “reactive species”, such as hydrogen peroxide, hypochlorous acid and peroxynitrite, are formed in vivo. Some of these molecules, e.g. superoxide and nitric oxide, can be physiologically useful, but they can also cause damage under certain circumstances. Excess production of reactive oxygen or nitrogen species (ROS, RNS), their production in inappropriate relative amounts (especially superoxide and NO ) or deficiencies in antioxidant defences may result in pathological stress to cells and tissues. This oxidative stress can have multiple effects. It can induce defence systems, and render tissues more resistant to subsequent insult. If oxidative stress is excessive or if defence and repair responses are inadequate, cell injury can be caused by such mechanisms as oxidative damage to essential proteins, lipid peroxidation, DNA strand breakage and base modification, and rises in the concentration of intracellular “free” Ca2+. Considerable evidence supports the view that oxidative damage involving both ROS and RNS is an important contributor to the development of atherosclerosis. Peroxynitrite (derived by reaction of superoxide with nitric oxide) and transition metal ions (perhaps released by injury to the vessel wall) may contribute to lipid peroxidation in atherosclerotic lesions.

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REFERENCES

  1. B. Halliwell and JMC Gutteridge. Free Radicals in Biology and Medicine, ed. 2 Clarendon Press, Oxford, 1989.

    Google Scholar 

  2. S. Moncada and A. Higgs. Molecular mechanisms and therapeutic strategies related to nitric oxide. FASEB J. 9:1319–1330 (1995).

    Google Scholar 

  3. I. Fridovich. Superoxide dismutases: An adaptation to a paramagnetic gas. J. Biol. Chem. 264:7761–7764 (1989).

    Google Scholar 

  4. J. T. Curnutte and B. M. Babior. Chronic granulomatous disease. Adv. Hum. Genet. 16:229–297 (1987).

    Google Scholar 

  5. G. A. C. Murrell, M. J. O. Francis, and L. Bromley. Modulation of fibroblast proliferation by oxygen free radicals. Biochem. J. 265:659–665 (1990).

    Google Scholar 

  6. B. Meier, H. Radeke, S. Selle, H. H. Raspe, G. Sies, K. Resch, and G. G. Habermehl. Human fibroblasts release reactive oxygen species in response to treatment with synovial fluids from patients suffering from arthritis. Free. Rad. Res. Commun. 8:149–160 (1990).

    Google Scholar 

  7. F. E. Maly. The B-lymphocyte: A newly-recognized source of reactive oxygen species with immunoregulatory potential. Free. Rad. Res. Commun. 8:143–148 (1990).

    Google Scholar 

  8. P. R. Gardner and I. Fridovich. Inactivation-reactivation of aconitase in Escherichia coli. A sensitive measure of superoxide radical. J. Biol. Chem. 267:8757–8763 (1992).

    Google Scholar 

  9. Y. Zhang, O. Marcillat, C. Giulivi, L. Ernster, and K. J. A. Davies. The oxidative inactivation of mitochondrial electron transport chain components and ATPase. J. Biol. Chem. 265:16330–16336 (1990).

    Google Scholar 

  10. M. Lepoivre, J. M. Flaman, P. Bobé, G. Lemaire, and Y. Henry. Quenching of the tyrosyl free radical of ribonucleotide reductase by nitric oxide. J. Biol. Chem. 269:21891–21897 (1994).

    Google Scholar 

  11. M. W. J. Cleeter, J. M. Cooper, V. M. Darley-Usmar, S. Moncada, and A. H. V. Schapira. Reversible inhibition of cytochrome c oxidase the terminal enzyme of the mitochondrial respiratory chain by nitric oxide. FEBS Lett. 345:50–54 (1994).

    Google Scholar 

  12. L. Castro, M. Rodriguez, and R. Radi. Aconitase is readily inactivated by peroxynitrite but not by its precursor nitric oxide. J. Biol. Chem. 269:29409–29415 (1994).

    Google Scholar 

  13. R. Radi, M. Rodriguez, L. Castro, and R. Telleri. Inhibition of mitochondrial electron transport by peroxynitrite. Arch. Biochem. Biophys. 303:89–95 (1994).

    Google Scholar 

  14. M. A. Packer, and M. P. Murphy. Peroxynitrite causes calcium efflux from mitochondria which is prevented by cyclosporin A. FEBS Lett. 345:237–240 (1994).

    Google Scholar 

  15. C. von Sonntag. The Chemical Basis of Radiation Biology. Taylor & Francis, London, 1987.

    Google Scholar 

  16. B. Halliwell, and J. M. C. Gutteridge. Role of free radicals and catalytic metal ions in human disease. Methods Enzymol. 186:1–85 (1990).

    Google Scholar 

  17. L. P. Candeias, K. B. Patel, M. R. L. Stratford, and P. Wardman. Free hydroxyl radicals are formed on reaction between the neutrophil-derived species superoxide anion and hypochlorous acid. FEBS Lett. 333:151–153 (1993).

    Google Scholar 

  18. B. Demple, and L. Harrison. Repair of oxidative damage to DNA: enzymology and biology. Annu. Rev. Biochem. 63:915–948 (1994).

    Google Scholar 

  19. T. Grune, T. Reinheckel, M. Joshi, and K. J. A. Davies. Proteolysis in cultured liver epithelial cells during oxidative stress. J. Biol. Chem. 270:2344–2351 (1995).

    Google Scholar 

  20. W. O. Carter, P. K. Narayanan, and J. P. Robinson. Intracellular hydrogen peroxide and superoxide anion detected in endothelial cells. J. Leukoc. Biol. 55:253–258 (1994).

    Google Scholar 

  21. W. Yang, and E. R. Block. Effect of hypoxia and reoxygenation on the formation and release of reactive oxygen species by porcine pulmonary artery endothelial cells. J. Cell Physiol. 164:414–423 (1995).

    Google Scholar 

  22. C. F. Babbs, M. D. Cregor, J. J. Turek, and S. F. Badylak. Endothelial superoxide production in buffer perfused rat lungs, demonstrated by a new histochemical technique. Lab. Invest. 65:484–496 (1991).

    Google Scholar 

  23. B. E. Britigan, T. L. Roeder, and D. M. Shasby. Insight into the nature and site of oxygen-centered free radical generation by endothelial cell monolayers using a novel spin trapping technique. Blood 79:699–707 (1992).

    Google Scholar 

  24. L. S. Terada, I. R. Willingham, M. E. Rosandich, J. A. Leff, G. W. Kindt, and J. E. Repine. Generation of superoxide anion by brain endothelial cell xanthine oxidase. J. Cell Physiol. 184:191–196 (1991).

    Google Scholar 

  25. T. Sundqvist. Bovine aortic endothelial cells release hydrogen peroxide. J. Cell Physiol. 148:152–156 (1991).

    Google Scholar 

  26. C. M. Arroyo, A. J. Carmichael, B. Bouscarel, J. H. Liang, and W. B. Weglicki. Endothelial cells as a source of oxygen-free radicals: An ESR study. Free Rad. Res. Commun. 9:287–296 (1990).

    Google Scholar 

  27. R. E. Ratych, R. S. Chuknyiska, and G. B. Bulkley. The primary localization of free radical generation after anoxia/reoxygenation in isolated endothelial cells. Surgery 102:122–126 (1987).

    Google Scholar 

  28. M. L. Schinetti, R. Sbarbati, and M. Scarlattini. Superoxide production by human umbilical vein endothelial cells in an anoxiareoxygenation model. Cardiovasc. Res. 23:76–79 (1989).

    Google Scholar 

  29. T. Matsubara, and M. Ziff. Increased superoxide anion release from human endothelial cells in response to cytokines. J. Immunol. 137:3295–3299 (1986).

    Google Scholar 

  30. Y. Hashimoto, K. Itoh, K. Nishida, T. Okano, Y. Miyazawa, and K. Okinaga. Rapid superoxide production by endothelial cells and their injury upon reperfusion. J. Surg. Res. 57:693–697 (1994).

    Google Scholar 

  31. Y. Ohara, T. E. Peterson, H. S. Sayegh, R. R. Subramanian, J. N. Wilcox, and D. G. Harrison. Dietary correction of hypercholesterolemia in the rabbit normalizes endothelial superoxide anion production. Circulation 92:898–903 (1995).

    CAS  PubMed  Google Scholar 

  32. J. L. Zweier, R. Broderick, P. Kuppusamy, S. Thompson-Gorman, and G. A. Lutty. Determination of the mechanism of free radical generation in human aortic endothelial cells exposed to anoxia and reoxygenation. J. Biol. Chem. 269:24156–24162 (1994).

    Google Scholar 

  33. A. Paler-Martinez, P. C. Panus, P. H. Chumley, U. Ryan, M. M. Hardy, and B. A. Freeman. Endogenous xanthine oxidase does not significantly contribute to vascular endothelial production of reactive oxygen species. Arch. Biochem. Biophys. 311:79–85 (1994).

    Google Scholar 

  34. K. M. Mohazzab-h, P. W. Kaminski, and M. S. Wolin. NADH oxidoreductase is a major source of superoxide anion in bovine coronary artery endothelium. Am. J. Physiol. 266:H2568–H2572 (1994).

    Google Scholar 

  35. P. J. Pagano, Y. Ito, K. Tornheim, P. M. Gallop, A. I. Tauber, and R. A. Cohen. An NADPH oxidase superoxide-generating system in the rabbit aorta. Am. J. Physiol. 268:H2274–H2280 (1995).

    Google Scholar 

  36. J. J. Zulueta, F. S. Yu, I. A. Hertig, V. J. Thannickal, and P. M. Hassoun. Release of hydrogen peroxide in response to hypoxiareoxygenation: Role of an NAD(P)H oxidase-like enzyme in endothelial cell plasma membrane. Am. J. Resp. Cell. Mol. Biol. 12:41–49 (1995).

    Google Scholar 

  37. D. A. Parks, Y. Yokoyama, S. Tan, E. Dickens, T. G. Cash and B. A. Freeman. Xanthine oxidase in the circulation of rats following hemorrhagic shock. Free Rad. Biol. Med. 15:407–414 (1993).

    Google Scholar 

  38. R. Miesel and M. Zuber. Elevated levels of xanthine oxidase in serum of patients with inflammatory and autoimmune rheumatic diseases. Inflammation 17:551–561 (1993).

    Google Scholar 

  39. S. Tan, S. Gelman, J. K. Wheat, and D. A. Parks. Circulating xanthine oxidase in human ischemia reperfusion. Southern Med. J. 88:479–482 (1995).

    Google Scholar 

  40. R. E. Huie, and S. Padmaja. The reaction of NO with superoxide. Free Rad. Res. Commun. 18:195–199 (1993).

    Google Scholar 

  41. W. W. Kooy, and J. A. Royal. Agonist-induced peroxynitrite production from endothelial cells. Arch. Biochem. Biophys. 310:352–359 (1994).

    Google Scholar 

  42. K. Nakazono, N. Watanabe, K. Matsuno, J. Sasaki, T. Sato, and M. Inoue. Does superoxide underlie the pathogenesis of hypertension? Proc. Natl. Acad. Sci. USA 88:10045–10048 (1991).

    Google Scholar 

  43. F. R. M. Laurindo, P. L. de Luz, L. Uint, T. F. Rocha, and R. G. Jaeger. Evidence for superoxide radical-dependent coronary vasospasm after angioplasty in intact dogs. Circulation 83:1705–1715 (1991).

    Google Scholar 

  44. J. S. Beckman, J. Chen, H. Ischiropoulous, and J. P. Crow. Oxidative chemistry of peroxynitrite. Meth. Enzymol. 233:229–240 (1994).

    Google Scholar 

  45. J. S. Beckman, T. W. Beckman, J. Chen, P. A. Marshall, and B. A. Freeman. Apparent hydroxyl radical production by peroxynitrite: Implications for endothelial injury from nitric oxide and superoxide. Proc. Natl. Acad. Sci. USA. 87:1620–1624 (1990).

    Google Scholar 

  46. A. van der Vliet, C. A. O'Neill, B. Halliwell, C. E. Cross and H. Kaur. Aromatic hydroxylation and nitration of phenylalanine and tyrosine by peroxynitrite. FEBS Lett. 339:89–92 (1994).

    Google Scholar 

  47. M. A. Moro, V. M. Darley-Usmar, I. Lizasoain, Y. Su, R. G. Knowles, M. W. Radomski, and S. M. Moncada. The formation of nitric oxide donors from peroxynitrite. Brit. J. Pharmacol. 116:1999–2004.

  48. M. A. Moro, V. M. Darley-Usmar, D. A. Goodwin, N. G. Read, R. Zamora-Pino, M. Feelish, M. Radomski, and S. Moncada. Paradoxical fate and biological action of peroxynitrite on human platelets. Proc. Natl. Acad. Sci. USA 91:6702–6706 (1994).

    Google Scholar 

  49. T. Abrahamsson, U. Brandt, S. L. Marklund, and P. O. Sjöqvist. Vascular bound recombinant extracellular superoxide dismutase type C protects against the detrimental effects of superoxide radicals on endothelium-dependent arterial relaxation. Circ. Res. 70:264–271 (1992).

    Google Scholar 

  50. L. M. Carlsson, J. Jonsson, T. Edlund, and S. L. Marklund. Mice lacking extracellular superoxide dismutase are more sensitive to hyperoxia. Proc. Natl. Acad. Sci. USA 92:6264–6268 (1995).

    Google Scholar 

  51. L. Jornot, and A. F. Junod. Variable glutathione levels and expression of antioxidant enzymes in human endothelial cells. Am. J. Physiol. 264:L482–L489 (1993).

    Google Scholar 

  52. A. Verkerk, and J. F. Jongkind. Vascular cells under peroxide induced oxidative stress: a balance study on in vitro peroxide handling by vascular endothelial and smooth muscle cells. Free Rad. Res. Commun. 17:121–132 (1992).

    Google Scholar 

  53. P. A. Hyslop, D. B. Hinshaw, W. A. Halsey JR et al. Mechanisms of oxidant-mediated cell injury. J. Biol. Chem. 263:1665–1675 (1988).

    Google Scholar 

  54. J. Varani, M. K. Dame, D. F. Gibbs, C. G. Taylor, J. M. Weinberg, J. Shayevitz, and P. A. Ward. Human umbilical vein endothelial cell killing by activated neutrophils. Lab. Invest. 66:708–714 (1992).

    Google Scholar 

  55. P. R. Kvietys, W. Inauen, B. R. Bacon, and M. B. Grisham. Xanthine oxidase-induced injury to endothelium: role of intracellular iron and hydroxyl radical. Am. J. Physiol. 257:H1640–H1646 (1989).

    Google Scholar 

  56. B. Halliwell, and J. M. C. Gutteridge. Oxygen-free radicals and iron in relation to biology and medicine: some problems and concepts. Arch. Biochem. Biophys. 246:501–508 (1986).

    Google Scholar 

  57. P. Biemond, H. G. Van Eijk, A. J. G. Swaak, and J. F. Koster. Iron mobilization from ferritin by superoxide derived from stimulated polymorphonuclear leukocytes: Possible mechanism in inflammation diseases. J. Clin. Invest. 73:1576–1579 (1984).

    Google Scholar 

  58. B. J. Bolann, and R. J. Ulvik. On the limited ability of superoxide to release iron from ferritin. Eur. J. Biochem. 193:899–904 (1990).

    Google Scholar 

  59. J. M. C. Gutteridge. Iron promoters of the Fenton reaction and lipid peroxidation can be released from haemoglobin by peroxides. FEBS Lett. 201:291–295 (1986).

    Google Scholar 

  60. A. Puppo, and B. Halliwell. Formation of hydroxyl radicals from hydrogen peroxide in the presence of iron: Is haemoglobin a biological Fenton catalyst? Biochem. J. 249:185–190 (1988).

    Google Scholar 

  61. M. R. Prasad, R. M. Engelman, R. M. Jones, and D. K. Das. Effects of oxyradicals on myoglobin. Deoxygenation, haem removal and iron release. Biochem. J. 263:731–736 (1989).

    Google Scholar 

  62. G. Balla, G. M. Vercellotti, U. Muller-Eberhard, J. Eaton, and H. S. Jacob. Exposure of endothelial cells to free heme potentiates damage mediated by granulocytes and toxic oxygen species. Lab. Invest. 64:648–655 (1991).

    Google Scholar 

  63. J. Balla, K. A. Nath, G. Balla, M. B. Juckett, H. S. Jacob, and G. M. Vercellotti. Endothelial cell heme oxygenase and ferritin induction in rat lung by hemoglobin in vivo. Am. J. Physiol. 268:L321–L327 (1995).

    Google Scholar 

  64. N. G. Abraham, Y. Lavrovsky, M. L. Schwartzman, R. A. Stoltz, R. D. Levere, M. E. Gerritsen, S. Shibahara, and A. Kappas. Transfection of the human heme oxygenase gene into rabbit coronary microvessel endothelial cells: protective effect against heme and hemoglobin toxicity. Proc. Natl. Acad. Sci. USA 92:6798–6802 (1995).

    Google Scholar 

  65. B. Halliwell, J. M. C. Gutteridge, and C. E. Cross. Free radicals, antioxidants and human disease: Where are we now? J. Lab. Clin. Med. 119:598–620 (1992).

    Google Scholar 

  66. B. Halliwell, O. I. Aruoma, G. Mufti, and A. Bomford. Bleomycindetectable iron in serum from leukaemic patients before and after chemotherapy. Therapeutic implications for treatment with oxidant-generating drugs. FEBS Lett. 241:202–204 (1988).

    Google Scholar 

  67. J. M. C. Gutteridge, P. G. Winyard, D. R. Blake, J. Lunec, S. Brailsford, and B. Halliwell. The behaviour of caeruloplasmin in stored human extracellular fluids in relation to ferroxidase II activity, lipid peroxidation, and phenanthroline-detectable copper. Biochem. J. 230:517–523 (1985).

    Google Scholar 

  68. P. J. Evans, R. W. Evans, A. Bomford, R. Williams, and B. Halliwell. Metal ions catalytic for free radical reactions in the plasma of patients with fulminant hepatic failure. Free Rad. Res. 20:119–133 (1994).

    Google Scholar 

  69. J. A. Swain, V. Darley-Usmar, and J. M. C. Gutteridge. Peroxynitrite releases copper from caeruloplasmin: implications for atherosclerosis. FEBS Lett. 342:49–52 (1994).

    Google Scholar 

  70. V. O'Donnell, and M. J. Burkitt. Mitochondrial metabolism of a hydroperoxide to free radicals in human endothelial cells; an electron spin resonance spin-trapping study. Biochem. J. 304:704–713 (1994).

    Google Scholar 

  71. S. Yla-Herttuala, W. Palinski, M. E. Rosenfield, S. Parthasarathy, T. E. Carew, S. Butler, J. L. Witztum and D. Steinberg. Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J. Clin. Invest. 84:1086–1099 (1989).

    Google Scholar 

  72. W. Palinski, M. E. Rosenfeld, S. Yla-Herttuala, G. C. Gurtner, S. S. Socher, S. W. Butler, S. Parthasarathy, T. E. Carew, D. Steinberg and J. L. Witztum. Low density lipoprotein undergoes oxidative modification in vivo. Proc. Natl. Acad. Sci. USA 86:1372–1376 (1989).

    Google Scholar 

  73. M. E. Haberland, C. L. Olch and A. M. Fogelman. Role of lysines in mediating interaction of modified low density lipoproteins with the scavenger receptor of human monocyte macrophages. J. Biol. Chem. 259:18;11305–11311 (1984).

    Google Scholar 

  74. S. Parthasarthy, D. J. Printz, D. Boyd, L. Joy and D. Steinberg. Macrophage oxidation of LDL generates a modified form recognised by the scavenger receptor. Arteriosclerosis 6:505–510 (1986).

    Google Scholar 

  75. J. T. Salonen, S. Yla-Herttuala, R. Yamamoto, S. Butler, H. Korpela, R. Salonen, K. Nyyssonen, W. Palinski and J. L. Witztum. Autoantibody against oxidised LDL and progression of carotid atherosclerosis. Lancet 339:883–885 (1992).

    Article  CAS  PubMed  Google Scholar 

  76. R. A. Riemersma, D. A. Wood, C. C. A. MacIntyre, R. A. Elton, K. F. Gey, and M. F. Oliver. Risk of angina pectoris and plasma concentrations of vitamins A, C and E and carotene. Lancet 337:1 (1991).

    Google Scholar 

  77. F. K. Gey. Ten year retrospective on the antioxidant hypothesis of arteriosclerosis. J. Nutr. Biochem. 6:206–236 (1995).

    Google Scholar 

  78. E. B. Rimm, M. J. Stampfer, A. Ascherio, E. Giovannucci, G. A. Colditz and W. C. Willett. Vitamin E consumption and the risk of coronary heart disease in men. N. Engl. J. Med. 328:1450–1456 (1993).

    Google Scholar 

  79. M. Dieber-Rotheneder, H. Puhl, G. Waeg, G. Striegl and H. Esterbauer. Effect of oral supplementation with D-α-tocopherol on the α-tocopherol content of human low density lipoproteins and resistance to oxidation. J. Lipid Res. 32:1325–1332 (1991).

    Google Scholar 

  80. P. D. Reaven, S. Parthasarathy, W. F. Beltz and J. L. Witztum. Effect of probucol dosage on plasma lipid and lipoprotein levels and on protection of low density lipoprotein against in vitro oxidation in humans. Arteriosclerosis and Thrombosis 12:318–324 (1992).

    Google Scholar 

  81. J. Regnstrom, G. Walldius, L. A. Carlson and J. Nilsson. Effect of probucol on the susceptibility of low density lipoprotein isolated from hypercholesterolemic patients to become oxidatively modified in vitro. Atherosclerosis 82:43–51 (1990).

    Google Scholar 

  82. E. Maggi, R. Bellazzi, F. Falaschi, A. Frattoni, G. Perani, G. Finardi, A. Gazo, M. Ni, D. Romanini and G. Bellomo. Enhanced LDL oxidation in uremic patients: and additional mechanisms for accelerated atherosclerosis. Kidney Int. 45:876–883 (1994).

    Google Scholar 

  83. J. Regnstrom, J. Nilsson, P. Tornvall, C. Landou and A. Hamsten. Susceptibility to low density lipoprotein oxidation and coronary atherosclerosis in man. Lancet 339:1183–1186 (1992).

    Google Scholar 

  84. H. Esterbauer, J. Gebicki, H. Puhl and G. Jurgens. The role of lipid peroxidation and antioxidants in the oxidative modification of LDL. Free Rad. Biol. Med. 13:341–390 (1993).

    Google Scholar 

  85. P. Reaven, S. Parthasarathy, B. J. Grasse, E. Miller, F. Alonazan, F. H. Mattson, J. C. Khoo, D. Steinberg and J. L. Witztum. Feasibility of using an oleate rich diet to reduce the susceptibility of LDL to oxidative modification in humans. Am. J. Clin. Nutr. 54:701–706 (1991).

    Google Scholar 

  86. C. E. Thomas and R. L. Jackson. Lipid hydroperoxide involvement in copper dependent and independent oxidation of low density lipoproteins. J. Pharmacol. Exp. Ther 256:1182–1188 (1991).

    Google Scholar 

  87. V. J. O'Leary, V. M. Darley-Usmar, L. J. Russell and D. Stone. Prooxidant effects of lipoxygenase-derived peroxides on the copperinitiated oxidation of low-density lipoprotein. Biochem. J. 282:631–634 (1992).

    Google Scholar 

  88. N. Hogg, C. Rice-Evans, V. Darley-Usmar, M. T. Wilson, G. Paganga and L. Bourne. The role of lipid hydroperoxides in the myoglobin-dependent oxidation of LDL. Arch. Biochem. Biophys. 314:39–44 (1994).

    Google Scholar 

  89. M. Iwatsuki, E. Niki, D. Stone and V. Darley-Usmar. α-Tocopherol mediated peroxidation in the copper(II) and metmyoglobin induced oxidation of human low density lipoprotein: the influence of lipid hydroperoxides. FEBS Lett. 360:271–276 (1995).

    Google Scholar 

  90. B. Frei and J. M. Gaziano. Content of antioxidants, preformed lipid hydroperoxides, and cholesterol as predictors of the susceptibility of human low density lipoprotein to metal-ion dependent and-independent oxidation. J. Lipid. Res. 34:2135–2145 (1993).

    Google Scholar 

  91. D. R. Smith, V. J. O'Leary and V. M. Darley-Usmar. The role of α-tocopherol as a peroxyl radical scavenger in human low density lipoprotein. Biochem. Pharmacol. 45:2195–2201 (1993).

    Google Scholar 

  92. Y. Yoshida and E. Niki. Oxidation of methyl linoleate in aqueous dispersions induced by copper and iron. Arch. Biochem. Biophys. 295:107–114 (1992).

    Google Scholar 

  93. V. A. Folcik, R. Nivar-Aristy, L. P. Krajewski, and M. K. Cathcart. Lipoxygenase contributes to the oxidation of lipids in human atherosclerotic plaques. J. Clin. Invest. 96:504–510 (1995).

    Google Scholar 

  94. S. Ylä-Herttuala, J. Luoma, H. Viita, T. Hiltunen, T. Sisto, and T. Nikkari. Transfer of 15-lipoxygenase gene into rabbit iliac arteries results in the appearance of oxidation-specific lipid-protein adducts characteristic of oxidized low density lipoprotein. J. Clin. Invest. 95:2692–2698 (1995).

    Google Scholar 

  95. Y. Yoshida, J. Tsuchiya and E. Niki. Interaction of α-tocopherol with copper and its effects on lipid peroxidation. Biochim. Biophys. Acta. 1200:85–92 (1994).

    Google Scholar 

  96. V. W. Bowry, D. Mohr, J. Cleary and R. Stocker. Prevention of tocopherol-mediated peroxidation in ubiquinol-10-free human low density lipoprotein. J. Biol. Chem. 270:5756–5763 (1995).

    Google Scholar 

  97. K. Mukai, H. Morimoto, Y. Okauchi, and S. Nagaoka. Kinetic study of reactions between tocopheroxyl radicals and fatty acids. Lipids 28:753–756 (1993).

    Google Scholar 

  98. H. Esterbauer, R. J. Schaur and H. Zollner. Chemistry and biochemistry of 4-hydroxynonenal, malondialdehyde and related aldehydes. Free Rad. Biol. Med. 11:81–128 (1991).

    Google Scholar 

  99. V. M. Darley-Usmar, A. Severn, V. J. O'Leary and M. Rogers. Treatment of macrophages with oxidised low density lipoprotein increases their intracellular glutathione content. Biochem. J. 278:429–434 (1991).

    Google Scholar 

  100. N. Gotoh, A. Graham, E. Niki and V. M. Darley-Usmar. Inhibition of glutathione synthesis increases the toxicity of oxidised LDL to human monocytes and macrophages. Biochem. J. 296:151–154 (1993).

    Google Scholar 

  101. G. Del Boccio, D. Lapenna, E. Porreca, A. Pennilli, F. Savini, P. Feliciani, G. Ricci and F. Cuccurullo. Aortic antioxidant defence mechanisms: time-related changes in cholesterol fed rabbits. Atherosclerosis 81:127–135 (1990).

    Google Scholar 

  102. J. D. Morrow, K. E. Hill, R. F. Burk, T. M. Mannour, K. F. Badr and L. J. Roberts II. A series of prostaglandin F2 like compounds are produced in vivo by humans by a non-cyclooxygenase, free radical catalysed mechanism. Proc. Natl. Acad. Sci. USA 87:9383–9387 (1990).

    Google Scholar 

  103. J. D. Morrow, J. A. Awad, T. Kato, K. Takahashi, K. F. Badr, L. J. Roberts II, and R. F. Burk. Formation of novel non-cyclooxygenase-derived prostanoids (F2-isoprostanes) in carbon tetrachloride hepatotoxicity. An animal model of lipid peroxidation. J. Clin. Invest. 90:2502–2507 (1992).

    Google Scholar 

  104. J. D. Morrow, K. P. Moore, J. A. Awad, M. D. Ravenscraft, G. Marini, K. F. Badr, R. Williams, and L. J. Roberts II: Marked overproduction of non-cycloxygenase derived prostanoids (F2-isoprostanes) in the hepatorenal syndrome. J. Lipid Mediat. 6:417–420 (1993).

    Google Scholar 

  105. S. M. Lynch, J. D. Morrow, L. J. Roberts II and B. Frei. Formation of non-cyclo-oxygenase-derived prostanoids (F2-isoprostanes) in plasma and low density lipoprotein exposed to oxidative stress in vitro. J. Clin. Invest. 93:998–1004 (1994).

    Google Scholar 

  106. J. D. Morrow, B. Frei, A. W. Longmire, J. M. Gaziano, S. M. Lynch, Y. Shyr, W. E. Strauss, J. A. Oates, and L. J. Roberts II: Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers. N. Engl. J. Med. 332:1198–1203 (1995).

    Google Scholar 

  107. K. P. Moore, V. Darley-Usmar, J. Morrow and L. J. Roberts II: Formation of F2-isoprostanes during the oxidation of human low density lipoprotein and plasma by peroxynitrite. Circ. Res. 77:335–341 (1995).

    Google Scholar 

  108. B. N. Ames. Endogenous oxidative DNA damage, aging, and cancer. Free Rad. Res. Commun. 7:121–128 (1989).

    Google Scholar 

  109. J. R. Totter. Spontaneous cancer and its possible relationship to oxygen metabolism. Proc. Natl. Acad. Sci. USA 77:1763–1767 (1980).

    Google Scholar 

  110. B. Halliwell. Free radicals and antioxidants: a personal view. Nutr. Rev. 52:253–265 (1994).

    Google Scholar 

  111. H. Sies. Oxidative Stress, Oxidants and Antioxidants, Academic Press, London and New York, 1991.

    Google Scholar 

  112. R. C. M. Siow, T. Ishii, H. Sato et al. Induction of the antioxidant stress proteins heme oxygenase-1 and MSP23 by stress agents and oxidized LDL in cultured vascular smooth muscle cells. FEBS Lett. 368:239–242 (1995).

    Google Scholar 

  113. S. Orrenius, D. J. McConkey, G. Bellomo, and P. Nicotera. Role of Ca2+ in toxic cell killing. Trends Pharmacol. Sci. 10:281–285 (1989).

    Google Scholar 

  114. R. L. Thies and A. P. Autor. Reactive oxygen injury to cultured pulmonary artery endothelial cells: Mediation by poly(ADP-ribose) polymerase activation causing NAD depletion and altered energy balance. Arch. Biochem. Biophys. 286:353–363 (1991).

    Google Scholar 

  115. R. G. Spragg. DNA strand break formation following exposure of bovine pulmonary artery and aortic endothelial cells to reactive oxygen products. Am. J. Respir. Cell. Mol. Biol. 4:4–10 (1991).

    Google Scholar 

  116. E. R. Block. Hydrogen peroxide alters the physical state and function of the plasma membrane of pulmonary artery endothelial cells. J. Cell. Physiol. 146:362–369 (1991).

    Google Scholar 

  117. M. D. Geeraerts, M. F. Ronveaux-Dupal, J. J. Lemasters, B. Herman. Cytosolic free Ca2+ and proteolysis in lethal oxidative injury in endothelial cells. Am. J. Physiol. 261:C889–C896 (1991).

    Google Scholar 

  118. S. P. Andreoli. Mechanisms of endothelial cell ATP depletion after oxidant injury. Pediat. Res. 25:97–101 (1989).

    Google Scholar 

  119. R. A. Kozar, B. J. McKeone, and H. J. Pownall. Free radicalinduced alterations in endothelial cell function. J. Surg. Res. 56:32–36 (1994).

    Google Scholar 

  120. B. Halliwell, and O. I. Aruoma. DNA damage by oxygen-derived species: Its mechanism and measurement in mammalian systems. FEBS Lett. 281:9–19 (1991).

    Article  CAS  PubMed  Google Scholar 

  121. T. N. Doan, D. L. Gentry, A. A. Taylor, and S. J. Elliott. Hydrogen peroxide activates agonist-sensitive Ca2+-flux pathways in canine venous endothelial cells. Biochem. J. 297:209–215 (1994).

    Google Scholar 

  122. K. D. Patel, G. A. Zimmerman, S. M. Prescott, R. P. McEver, and T. M. McIntyre. Oxygen radicals induce human endothelial cells to express GMP-140 and bind neutrophils. J. Cell Biol. 112:749–759 (1991).

    Google Scholar 

  123. M. A. Shatos, J. M. Doherty, and J. C. Hoak. Alterations in human vascular endothelial cell function by oxygen free radicals. Platelet adherence and prostacyclin release. Arteriosclerosis Thrombosis 11:594–601 (1991).

    Google Scholar 

  124. C. Weber, W. Erl, A. Pietsch, M. Strobel, H. W. Ziegler-Heitbrock, and P. C. Weber. Antioxidants inhibit monocyte adhesion by suppressing nuclear factor-κB mobilization and induction of vascular cell adhesion molecule-1 in endothelial cells stimulated to generate radicals. Arteriosclerosis Thrombosis 14:1665–1673 (1994).

    Google Scholar 

  125. G. M. Vercellotti, S. P. Severson, P. Duane, and C. F. Moldow. Hydrogen peroxide alters signal transduction in human endothelial cells. J. Lab. Clin. Med. 117:15–24 (1991).

    Google Scholar 

  126. S. K. Lo, K. Janakidevi, L. Lai, and S. B. Malik. Hydrogen peroxide-induced increase in endothelial adhesiveness is dependent on ICAM-1 activation. Am. J. Physiol. 264:L406–L412 (1993).

    Google Scholar 

  127. V. Natarajan, M. M. Taher, B. Roehm, N. L. Parinandi, H. H. O. Schmid, Z. Kiss, J. G. N. Garcia. Activation of endothelial cell phospholipase D by hydrogen peroxide and fatty acid hydroperoxide. J. Biol. Chem. 268:930–937 (1993).

    Google Scholar 

  128. M. S. Lewis, R. E. Whatley, P. Cain, T. M. McIntyre, S. M. Prescott, and G. A. Zimmerman. Hydrogen peroxide stimulates the synthesis of platelet-activating factor by endothelium and induces endothelial cell-dependent neutrophil adhesion: J. Clin. Invest. 82:2045–2055 (1988).

    Google Scholar 

  129. M. Suzuki, W. Inauen, P. R. Kvietys, M. B. Grisham, C. Meininger, M. E. Schelling, H. J. Granger, D. N. Granger. Superoxide mediates reperfusion-induced leukocyte-endothelial cell interactions. Am. J. Physiol. 257:H1740–H1745 (1989).

    Google Scholar 

  130. J. R. Bradley, D. R. Johnson, and J. S. Pober. Endothelial activation by hydrogen peroxide. Am. J. Path. 142:1598–1609 (1993).

    Google Scholar 

  131. H. A. Lehr, A. M. Olofsson, T. E. Carew, P. Vajkoczy, U. H. von Andrian, C. Hübner, M. C. Berndt, D. Steinberg, K. Messmer, K. E. Arfors. P-selectin mediates the interaction of circulating leukocytes with platelets and microvascular endothelium in response to oxidized lipoprotein in vivo. Lab. Invest. 71:380–386 (1994).

    Google Scholar 

  132. C. S. Boyer, G. L. Bannenberg, E. P. A. Neve, A. Ryrfeldt and P. Moldeus. Evidence for the activation of the signal-responsive phospholipase A2 by exogenous hydrogen peroxide. Biochem. Pharmacol. 50:753–761 (1995).

    Google Scholar 

  133. C. M. Tan, S. Xenoyannis and R. D. Feldman. Oxidant stress enhances adenylyl cyclase activation. Circ. Res. 77:710–717 (1995).

    Google Scholar 

  134. J. V. Meharg, J. McGowan-Jordan, A. Charles, J. T. Parmelees, M. V. Cutaia, and S. Rounds. Hydrogen peroxide stimulates sodium-potassium pump activity in cultured pulmonary artery endothelial cells. Am. J. Physiol. 265:L613–L621 (1993).

    Google Scholar 

  135. J. Varani, and P. A. Ward. Mechanisms of endothelial cell injury in acute inflammation. Shock 2:311–319 (1994).

    Google Scholar 

  136. D. W. Granger, and P. Kubes. The microcirculation and inflammation: modulation of leukocyte-endothelial cell adhesion. J. Leukoc. Biol. 55:662–675 (1994).

    Google Scholar 

  137. M. C. Carreras, G. A. Pargament, S. D. Catz, J. J. Poderoso, and A. Boveris. Kinetics of nitric oxide and hydrogen peroxide production and formation of peroxynitrite during the respiratory burst of human neutrophils. FEBS Lett. 341:65–68 (1994).

    Google Scholar 

  138. S. J. Weiss. Tissue destruction by neutrophils. N. Engl. J. Med. 320:365–376 (1989).

    Google Scholar 

  139. N. M. Domigan, T. S. Charlton, M. W. Duncan, C. C. Winterbourn, and A. J. Kettle. Chlorination of tyrosyl residues in peptides by myeloperoxidase and human neutrophils. J. Biol. Chem. 270:16542–16548 (1995).

    Google Scholar 

  140. A. van der Vliet, M. L. Hu, C. A. O'Neill, C. E. Cross, B. Halliwell. Interactions of human blood plasma with hydrogen peroxide and hypochlorous acid. J. Lab. Clin. Med. 1124:701–707 (1994).

    Google Scholar 

  141. R. Ross. The pathogenesis of atherosclerosis, a perspective for the 1990s. Nature 362:801–809 (1993).

    Article  CAS  PubMed  Google Scholar 

  142. Y. Ohara, T. E. Peterson and D. G. Harrison. Hypercholesterolemia increases endothelial superoxide anion production. J. Clin. Invest. 91:2541–2551 (1993).

    Google Scholar 

  143. J. W. Heinecke, H. Rosen, L. A. Suzuki, and A. Chait. The role of sulfur-containing amino acids in superoxide production and modification of low density lipoprotein by arterial smooth muscle cells. J. Biol. Chem. 262:10098–10103 (1987).

    Google Scholar 

  144. C. P. Sparrow, and J. Olszewski. Cellular oxidation of low-density lipoprotein is caused by thiol production in media containing transition metals. J. Lipid Res. 34:1219–1228 (1993).

    Google Scholar 

  145. A. Graham, J. L. Wood, V. J. O'Leary, and D. Stone. Human (THP-1) macrophages oxidize LDL by a thiol-dependent mechanism. Free Rad. Res. 21:295–308 (1994).

    Google Scholar 

  146. F. Liao, J. A. Berliner, M. Mehrabian, M. Navab, L. L. Demer, A. J. Lusis, and A. M. Fogelman. Minimally modified low density lipoprotein is biologically active in vivo in mice. J. Clin. Invest. 87:2253–2257 (1991).

    Google Scholar 

  147. M. E. Rosenfeld. Oxidized LDL affects multiple atherogenic cellular responses. Circulation 83:2137–2140 (1991).

    Google Scholar 

  148. T. Collins. Endothelial nuclear factor-κB and the initiation of the atherosclerotic lesion. Lab. Invest. 68:499–508 (1993).

    Google Scholar 

  149. A. J. Lusis, and M. Navab. Lipoprotein oxidation and gene expression in the artery wall. Biochem. Pharmacol. 46:2119–2126 (1993).

    Google Scholar 

  150. M. A. Warso, and W. E. M. Lands. Lipid peroxidation in relation to prostacyclin and thromboxane physiology and pathophysiology. Br. Med. Bull. 39:277–280 (1983).

    Google Scholar 

  151. J. A. Holland, K. A. Pritchard, W. J. Rogers, and M. B. Stemerman. Perturbation of cultured human endothelial cells by atherogenic levels of low density lipoprotein. Am. J. Pathol. 132:474–478 (1988).

    Google Scholar 

  152. M. Yokode, T. Kita, Y. Kikawa, T. Ogorochi, S. Narumiya, and C. Kawai. Stimulated arachidonate metabolism during foam cell transformation of mouse peritoneal macrophages with oxidized low density lipoprotein. J. Clin. Invest. 81:720–729 (1988).

    Google Scholar 

  153. C. A. Smith, M. J. Mitchinson, O. I. Aruoma, and B. Halliwell. Stimulation of lipid peroxidation and hydroxyl radical generation by the contents of human atherosclerotic lesions. Biochem. J. 286:901–905 (1992).

    Google Scholar 

  154. C. J. Lamb, M. J. Mitchinson, and D. S. Leake. Transition metal ions within human atherosclerotic lesions can catalyze the oxidation of low density lipoprotein by macrophages. FEBS Lett. 374:12–16 (1995).

    Google Scholar 

  155. J. Swain, and J. M. C. Gutteridge. Pro-oxidant iron and copper, with ferroxidase and xanthine oxidase activities, in human atherosclerotic material. FEBS Lett. 368:513–515 (1995).

    Google Scholar 

  156. H. F. Hoff, and J. O'Neill. Extracts of human atherosclerotic lesions can modify low density lipoproteins leading to enhanced uptake by macrophages. Atherosclerosis 70:29–41 (1988).

    Google Scholar 

  157. P. J. Evans, C. Smith, M. J. Mitchinson, and B. Halliwell: Metal ion release from mechanically-disrupted human arterial wall. Implications for the development of atherosclerosis. Free Rad. Res. 23:465–469 1995.

    Google Scholar 

  158. A. Graham, N. Hogg, B. Kalyanaraman, V. O'Leary, V. Darley-Usmar, and S. Moncada. Peroxynitrite modification of low-density lipoprotein leads to recognition by the macrophage scavenger receptor. FEBS Lett. 330:181–185 (1993).

    Google Scholar 

  159. J. S. Beckman, Y. Z. Ye, P. G. Anderson, J. Chen, M. A. Accavatti, M. M. Tarpey, and C. R. White. Extensive nitration of protein tyrosines in human atherosclerosis detected by immunohistochemistry. Biol. Chem. Hoppe Seyler 375:81–88 (1994).

    Google Scholar 

  160. J. Kanner, S. Harel, and R. Granit. Nitric oxide as an antioxidant. Arch. Biochem. Biophys. 289:130–136 (1991).

    Google Scholar 

  161. G. Dee, C. Rice-Evans, S. Obeyesekara et al. The modulation of ferryl myoglobin formation and its oxidative effects on low density lipoproteins by nitric oxides. FEBS Lett. 294:38–42 (1991).

    Google Scholar 

  162. D. A. Wink, I. Hanbauer, M. C. Krishna, W. De Gratt, J. Gamson, and J. B. Mitchell. Nitric oxide protects against cellular damage and cytoxicity from reactive oxygen species. Proc. Natl. Acad. Sci. USA 90:9813–9817 (1993).

    Google Scholar 

  163. B. Halliwell. Superoxide, iron, vascular endothelium and reperfusion injury. Free Rad. Res. Commun. 5:315–318 (1989).

    Google Scholar 

  164. A. van der Vliet, D. Smith, C. A. O'Neill, H. Kaur, V. Darley-Usmar, C. E. Cross, and B. Halliwell. Interactions of peroxynitrite with human plasma and its constituents: oxidative damage and antioxidant depletion. Biochem. J. 303:295–301 (1994).

    Google Scholar 

  165. S. Padmaja, and R. E. Huie. The reaction of nitric oxide with organic peroxyl radicals. Biochem. Biophys. Res. Commun. 195:539–544 (1993).

    Google Scholar 

  166. N. Hogg, B. Kalyanaraman, J. Joseph, A. Struck, and S. Parthasarathy. Inhibition of low-density lipoprotein oxidation by nitric oxide. FEBS Lett. 334:170–174 (1993).

    Google Scholar 

  167. J. Gaboury, R. C. Woodman, D. N. Granger, P. Reinhardt, and P. Kubes. Nitric oxide prevents leukocyte adherence: role of superoxide. Am. J. Physiol. 265:H862–H867 (1993).

    Google Scholar 

  168. H. Rubbo, R. Radi, M. Trujillo, R. Telleri, B. Kalyanaraman, S. Barnes, M. Kirk, and B. A. Freeman. Nitric oxide regulation of superoxide and peroxynitrite-dependent lipid peroxidation. J. Biol. Chem. 269:26066–26075 (1994).

    Google Scholar 

  169. A. Daugherty, J. L. Dunn, D. L. Rateri, and J. W. Heinecke. Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions. J. Clin. Invest. 94:437–444 (1994).

    Google Scholar 

  170. M. I. Savenkova, D. M. Mueller, and J. W. Heinecke. Tyrosyl radical generated by myeloperoxidase is a physiological catalyst for the initiation of lipid peroxidation in low density lipoprotein. J. Biol. Chem. 269:20394–20400 (1994).

    Google Scholar 

  171. J. Eiserich, J. Butler, A. van der Vliet, C. E. Cross, and B. Halliwell. Nitric oxide rapidly scavenges tyrosine and tryptophan radicals. Biochem. J. 310:745–749 (1995).

    Google Scholar 

  172. M. T. Yates, L. E. Lambert, J. P. Whitten et al. A protective role for nitric oxide in the oxidative modification of low density lipoproteins by mouse macrophages. FEBS Lett. 309:135–138 (1992).

    Google Scholar 

  173. W. Jessup, D. Mohr, S. P. Gieseg, R. T. Dean, and R. Stocker. The participation of nitric oxide in cell free-and its restriction of macrophage-mediated oxidation of low density lipoprotein. Biochim. Biophys. Acta 1880:73–82 (1992).

    Google Scholar 

  174. U. Malo-Ranta, S. Ylä-Herttuala, T. Metsä-Ketelä, O. Jaakkola, E. Moilanen, P. Vuorinen, and T. Nikkari. Nitric oxide donor GEA 3162 inhibits endothelial cell-mediated oxidation of low density lipoprotein. FEBS Lett. 337:179–183 (1994).

    Google Scholar 

  175. W. C. Tarry, and R. G. Makhoul. L-arginine improves endothelium-dependent vasorelaxation and reduces intimal hyperplasia after balloon angioplasty. Arteriosclerosis Thrombosis 14:938–943 (1994).

    Google Scholar 

  176. J. P. Cooke, A. H. Singer, P. Tsao, P. Zera, R. A. Rowan, and M. E. Billingham. Antiatherogenic effects of L-arginine in the hypercholesterolemic rabbit. J. Clin. Invest. 90:1168–1172 (1992).

    Google Scholar 

  177. H. E. Von der Leyen, G. H. Gibbons, Y. Morishita, N. P. Lewis, L. Zhang, M. Nakajima, Y. Kaneda, J. P. Cooke, and V. J. Dzau. Gene therapy inhibiting neointimal vascular lesion: in vivo transfer of endothelial cell nitric oxide synthase gene. Proc. Natl. Acad. Sci. USA 92:1137–1141 (1995).

    Google Scholar 

  178. V. Darley-Usmar, H. Wiseman, and B. Halliwell. Nitric oxide and oxygen radicals: a question of balance. FEBS Lett. 369:131–135 (1995).

    Google Scholar 

  179. K. M. Naseem, and K. R. Bruckdorfer. Hydrogen peroxide at low concentrations strongly enhances the inhibitory effect of nitric oxide on platelets. Biochem. J. 310:149–153 (1995).

    Google Scholar 

  180. R. W. Alexander. Hypertension and the pathogenesis of atherosclerosis. Hypertension 25:155–161 (1995).

    CAS  PubMed  Google Scholar 

  181. D. Steinberg. Clinical trials of antioxidants in atherosclerosis: are we doing the right thing? Lancet 346:36–38 (1995).

    Google Scholar 

  182. M. A. Marletta. Approaches to selective inhibition of nitric oxide synthase. J. Med. Chem. 37:1899–1907 (1994).

    Google Scholar 

  183. E. S. Furfine, H. F. Harmon, J. E. Paith, R. G. Knowles, M. Salter, R. J. Kiff, C. Durthy, R. Hazelwood, J. A. Oplinger, and E. P. Garvey. Potent and selective inhibition of human nitric oxide synthases. Selective inhibition of neuronal nitric oxide synthase by S-methyl-L-thiocitrulline and S-ethyl-L-thiocitrulline. J. Biol. Chem. 269:26677–26683 (1994).

    Google Scholar 

  184. R. C. Babbedge, P. A. Bland-Ward, S. L. Hart, and P. K. Moore. Inhibition of rat cerebellar nitric oxide synthase by 7-nitro indazole and related substituted indazoles. Br. J. Pharmacol. 110:225–228 (1993).

    Google Scholar 

  185. A. Petros, G. Lamb, A. Leone, S. Moncada, D. Bennett and P. Valance. Effects of NO synthase inhibitors in humans with septic shock. Cardiovasc. Res. 28:343–339 (1994).

    Google Scholar 

  186. T. Munzel, H. Sayegh, B. A. Freeman, M. M. Tarpey, and D. G. Harrison. Evidence for enhanced vascular superoxide anion production in nitrate tolerance. A novel mechanism underlying tolerance and cross-tolerance. J. Clin. Invest. 95:187–194 (1995).

    Google Scholar 

  187. M. Radomski, D. Rees, A. Dutra and S. Moncada. S-nitrosoglutathione inhibits platelet activation in vitro and in vivo. Br. J. Pharmacol. 107:745–749 (1992).

    Google Scholar 

  188. J. R. Connor, P. T. Manning, S. L. Settle, W. M. Moore, G. M. Jerome, R. K. Webber, F. S. Tjoeng and M. G. Currie. Suppression of adjuvant-induced arthritis by selective inhibition of inducible nitric oxide synthase. Eur. J. Pharm. 273:15–24 (1995).

    Google Scholar 

  189. H. Drexler, A. M. Zeiher, K. Meinzer and H. Just. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine. Lancet 338:1546–1550 (1991).

    Article  CAS  PubMed  Google Scholar 

  190. M. Inoue, N. Watanabe, Y. Morino, Y. Tanaka, T. Amachi, and J. Sasaki. Inhibition of oxygen toxicity by targeting superoxide dismutase to endothelial cell surface. FEBS Lett. 269:89–92 (1990).

    Google Scholar 

  191. T. P. Kasten, S. L. Settle, T. P. Misko, D. P. Riley, R. H. Weiss, M. G. Currie, and G. A. Nickols. Potentiation of nitric oxide-mediated vascular relaxation by SC52608, a superoxide dismutase mimic. Proc. Soc. Exp. Biol. Med. 208:170–177 (1995).

    Google Scholar 

  192. C. R. White, T. A. Brock, L. Y. Chang, J. Crapo, P. Briscoe, D. Ku, W. A. Bradley, S. H. Gianturco, J. Gore, B. A. Freeman, and M. M. Tarpey. Superoxide and peroxynitrite in atherosclerosis. Proc. Natl. Acad. Sci. USA 91:1044–1048 (1994).

    Google Scholar 

  193. T. E. Carew, D. C. Schwenke and D. Steinberg. Antiatherogenic effect of probucol unrelated to its hypocholesterolemic effect: evidence that antioxidants in vivo can selectively inhibit low density lipoprotein degradation in macrophage-rich fatty streaks and slow the progression of atherosclerosis in Watanabe heritable hyperlipidemic rabbits. Proc. Natl. Acad. Sci. USA 84:7725–7729 (1987).

    Google Scholar 

  194. V. J. O'Leary, T. Tilling, G. Fleetwood, D. Stone and V. M. Darley-Usmar. The resistance of low density lipoprotein to oxidation promoted by copper and its use as an index of antioxidant therapy. Atherosclerosis 119:169–179 (1995).

    Google Scholar 

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Darley-Usmar, V., Halliwell, B. Blood Radicals: Reactive Nitrogen Species, Reactive Oxygen Species, Transition Metal Ions, and the Vascular System. Pharm Res 13, 649–662 (1996). https://doi.org/10.1023/A:1016079012214

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