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New Approaches to the Prevention of Atherosclerosis

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Summary

In recent years, remarkable progress has been made in the prevention and treatment of atherosclerosis. However, much of the research has been devoted to the investigation of lipid metabolism and lipid-lowering drugs. This review highlights some recent topics in both experimental and clinical investigations, with emphasis on studies other than those on lipid-lowering drugs. These topics include oxidative modification of lipoproteins, hyperfibrinogenaemia, hyperhomo-cysteinaemia, female sex hormones and endothelium-derived relaxing factor (or nitric oxide). Some of these approaches have already been applied in the clinic.

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References

  1. Steinberg D, Parthasarathy S, Carew TE, et al. Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989; 320: 915–24

    PubMed  CAS  Google Scholar 

  2. Esterbauer H, Gebicki J, Puhl H, et al. The role of lipid peroxidation and antioxidants in oxidative modification of LDL. Free Radical Biol Med 1992; 13: 341–90

    CAS  Google Scholar 

  3. Naito M, Kuzuya M, Kuzuya F. Effects of oxidized low density lipoproteins on vascular wall cells. J Jpn Atheroscler Soc 1990; 18: 827–31

    CAS  Google Scholar 

  4. Naito M, Kuzuya M, Iguchi I. Mechanisms of endothelial cell injury induced by oxidatively modified LDL. J Jpn Atheroscler Soc 1994; 22: 257–62

    CAS  Google Scholar 

  5. Kuzuya M, Naito M, Funaki C, et al. Lipid peroxide and transition metals are required for the toxicity of oxidized low density lipoprotein to cultured endothelial cells. Biochim Biophys Acta 1991; 1096: 155–61

    PubMed  CAS  Google Scholar 

  6. Naito M, Yamada K, Hayashi T, et al. Comparative toxicity of oxidatively modified low-density lipoprotein and lysophos-phatidylcholine in cultured vascular endothelial cells. Heart Vessels 1994; 9: 183–7

    PubMed  CAS  Google Scholar 

  7. Rosenfeld ME, Palinski W, Ylä-Herttuala S, et al. Distribution of oxidation specific Hpid-protein adducts and apolipoprotein in atherosclerotic lesions of varying severity from WHHL rabbits. Arteriosclerosis 1990; 10: 336–49

    PubMed  CAS  Google Scholar 

  8. Ylä-Herttuala S, Palinski W, Rosenfeld ME, et al. Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J Clin Invest 1989; 84: 1086–95

    PubMed  Google Scholar 

  9. Parthasarathy S, Khoo JC, Miller E, et al. Low density lipoprotein rich in oleic acid is protected against oxidative modification: implications for dietary prevention of atherosclerosis. Proc Natl Acad Sci USA 1990; 87: 3894–8

    PubMed  CAS  Google Scholar 

  10. Bonanome A, Pagnan A, Biffanti S, et al. Effect of dietary monounsaturated and polyunsaturated fatty acids on the susceptibility of plasma low density lipoproteins to oxidative modification. Arterioscler Thromb 1992; 12: 529–33

    PubMed  CAS  Google Scholar 

  11. Kleinveld HA, Naber AHJ, Stalenhoef AFH, et al. Oxidation resistance, oxidation rate, and extent of oxidation of human low-density lipoprotein depend on the ratio of oleic acid content to linoleic acid content: studies in vitamin E deficient subjects. Free Radical Biol Med 1993; 15: 273–80

    CAS  Google Scholar 

  12. Rice-Evans CA, Diplock A. Current status of antioxidant therapy. Free Radical Biol Med 1993; 15: 77–96

    CAS  Google Scholar 

  13. Babiy AV, Gebicki JM, Sullivan DR. Vitamin E content and low density lipoprotein oxidizability induced by free radicals. Atherosclerosis 1990; 81: 175–82

    PubMed  CAS  Google Scholar 

  14. Belcher JD, Balla J, Balla G, et al. Vitamin E, LDL, and endothelium: brief oral vitamin supplementation prevents oxidized LDL-mediated vascular injury in vitro. Arterioscler Thromb 1993; 13: 1779–89

    PubMed  CAS  Google Scholar 

  15. Jialal I, Norkus EP, Cristol L, et al. β-Carotene inhibits the oxidative modification of low density lipoprotein. Biochim Biophys Acta 1991; 1086: 134–8

    PubMed  CAS  Google Scholar 

  16. Reaven PD, Khouw A, Beltz W, et al. Effect of dietary antioxidant combinations in humans: protection of LDL by vitamin E, but not by β-carotene. Arterioscler Thromb 1993; 13: 601–8

    PubMed  CAS  Google Scholar 

  17. Princen H, van Poppel G, Vogelezang et al. Supplementation with vitamin E but not β-carotene in vivo protects low density lipoprotein from lipid peroxidation in vitro: effects of cigarette smoking. Arterioscler Thromb 1992; 12: 554–62

    PubMed  CAS  Google Scholar 

  18. Jialal I, Vega GL, Grundy SM. Physiologic levels of ascorbate inhibit the oxidative modification of low density lipoprotein. Atherosclerosis 1990; 82: 185–91

    PubMed  CAS  Google Scholar 

  19. Jialal I, Grundy SM. Preservation of the endogenous antioxidants in low density lipoprotein by ascorbate but not probucol during oxidative modification. J Clin Invest 1991; 87: 597–601

    PubMed  CAS  Google Scholar 

  20. Jialal I, Grundy SM. Effects of combined supplementation with α-tocopherol, ascorbate, and beta carotene on low-density lipoprotein oxidation. Circulation 1993; 88: 2780–6

    PubMed  CAS  Google Scholar 

  21. Frankel EN, Kanner J, German JB. Inhibition of oxidation of human low-density lipoprotein by phenolic substances in red wine. Lancet 1993; 341: 454–7

    PubMed  CAS  Google Scholar 

  22. Giroux LM, Davignon J, Naruszewicz M. Simvastatin inhibits the oxidation of low-density lipoproteins by activated human monocyte-derived macrophages. Biochim Biophys Acta 1993; 1165: 335–8

    PubMed  CAS  Google Scholar 

  23. Aviram M, Dankner G, Cogan U, et al. Lovastatin inhibits lowdensity lipoprotein oxidation and alters its fluidity and uptake by macrophages: in vitro and in vivo studies. Metabolism 1992; 41: 229–35

    PubMed  CAS  Google Scholar 

  24. Naito M, Hayashi T, Yamada K, et al. Protective effects of idebenone on vascular endothelial cells against toxicity induced by oxidatively modified low density lipoprotein. Artery 1993; 20: 314–23

    PubMed  CAS  Google Scholar 

  25. de Graaf J, Hak-Lemmers HLM, Hectors MPC, et al. Enhanced susceptibility to in vitro oxidation of the dense low density lipoprotein subfraction in healthy subjects. Arterioscler Thromb 1991; 11: 298–306

    PubMed  Google Scholar 

  26. Tribble DL, Holl LG, Wood PD, et al. Variations in oxidative susceptibility among six low density lipoprotein subfractions of differing density and particle size. Atherosclerosis 1992; 93: 189–99

    PubMed  CAS  Google Scholar 

  27. Chait A, Brazg RL, Tribble DL. Susceptibility of small, dense, low-density lipoproteins to oxidative modification in subjects with the atherogenic lipoprotein phenotype, pattern B. Am J Med 1993; 94: 350–6

    PubMed  CAS  Google Scholar 

  28. Austin MA, Krauss RM. Genetic control of low density lipoprotein subclasses. Lancet 1986; 2: 592–5

    PubMed  CAS  Google Scholar 

  29. Riemersma R. Risk of angina pectoris and plasma concentration of vitamin and E and carotene. Lancet 1991; 337: 1–5

    PubMed  CAS  Google Scholar 

  30. Chow CK, Changchit C, Bridges R, et al. Lower levels of vitamin and carotene in plasma of cigarette smokers. J Am Coll Nutr 1986; 5: 305–12

    PubMed  CAS  Google Scholar 

  31. Verlangieri AJ, Bush MJ. Effects of d-α-tocopherol supplementation on experimentally induced primate atherosclerosis. J Am Coll Nutr 1992; 11: 131–8

    PubMed  CAS  Google Scholar 

  32. Williams RJ, Motteram JM, Sharp CH, et al. Dietary vitamin E and the attenuation of early lesion development in modified Watanabe rabbits. Atherosclerosis 1992; 94: 153–9

    PubMed  CAS  Google Scholar 

  33. Stampfer MJ, Hennekens CH, Manson JE, et al. Vitamin E consumption and the risk of coronary disease in women. N Engl J Med 1993; 328: 1444–9

    PubMed  CAS  Google Scholar 

  34. Rimm EB, Stampfer MJ, Ascherio A, et al. Vitamin E consumption and the risk of coronary disease in men. N Engl J Med 1993; 328: 1450–6

    PubMed  CAS  Google Scholar 

  35. Gaziano J, Manson J, Ridker J, et al. Dietary antioxidants and cardiovascular disease. Biochim Biophys Acta 1992; 669: 249–58

    CAS  Google Scholar 

  36. Hertog MGL, Feskens EJM, Hollman PCH, et al. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet 1993; 342: 1007–11

    PubMed  CAS  Google Scholar 

  37. Kuzuya M, Kuzuya F. Probucol as an antioxidant and antiatherogenic drug. Free Radical Biol Med 1993; 14: 67–77

    CAS  Google Scholar 

  38. Kita T, Nagano Y, Yokode M, et al. Probucol prevents the progression of atherosclerosis in Watanabe heritable hyper-lipidemic rabbit, an animal model for familial hypercholesterolemia. Proc Natl Acad Sci USA 1987; 84: 5928–31

    PubMed  CAS  Google Scholar 

  39. Schneider JE, Berk Gravanis MB, et al. Probucol decreases neointimal formation in a swine model of coronary artery balloon injury: a possible role for antioxidants in restenosis. Circulation 1993; 88: 628–37

    PubMed  CAS  Google Scholar 

  40. Daugherty A, Zweifel BS, Schonfeld G. Probucol attenuates the development of aortic atherosclerosis in cholesterol-fed rabbits. Br J Pharmacol 1989; 98: 612–8

    PubMed  CAS  Google Scholar 

  41. Sasahara M, Raines EW, Chait A, et al. Inhibition of hypercholesterolemia-induced atherosclerosis in the nonhuman primate by probucol: I. Is the extent of atherosclerosis related to resistance of LDL to oxidation? J Clin Invest 1994; 94: 155–64

    PubMed  CAS  Google Scholar 

  42. Ferns GA, Forster L, Stewart-Lee A, et al. Probucol inhibits neointimal thickening and macrophage accumulation after balloon injury in the cholesterol-fed rabbit. Proc Natl Acad Sci USA 1992; 89: 11312–6

    PubMed  CAS  Google Scholar 

  43. Stein Y, Stein Delplanque et al. Lack of effect of probucol on atheroma formation in cholesterol-fed rabbits kept at comparable plasma cholesterol levels. Atherosclerosis 1989; 75: 145–55

    PubMed  CAS  Google Scholar 

  44. Yamamoto A, Matsuzawa Y, Yokoyama S et al. Effects of probucol on xanthomata regression in familial hypercholesterolemia. Am J Cardiol 1986; 57: 29H–35H

    PubMed  CAS  Google Scholar 

  45. Elinder LS, Walldius G. Antioxidants and atherosclerosis progression: unresolved questions. Curr Opin Lipidol 1994; 5: 265–8

    PubMed  CAS  Google Scholar 

  46. Mao SJT, Yates MT, Parker RA, et al. Attenuation of atherosclerosis in a modified strain of hypercholesterolemic Watanabe rabbits with use of a probucol analogue (MDL 29, 311) that does not lower serum cholesterol. Arterioscler Thromb 1991; 11: 1266–75

    PubMed  CAS  Google Scholar 

  47. O’Brien K, Nagano Y, Gown A, et al. Probucol treatment affects the cellular composition but not anti-oxidized low density lipoprotein immunoreactivity of plaques from Watanabe heritable hyperlipidemic rabbits. Arterioscler Thromb 1991; 11: 751–9

    PubMed  Google Scholar 

  48. Sirtori CS, Sirtori M, Calabresi L, et al. Changes in high-density lipoprotein subfraction distribution and increased cholesteryl ester transfer after probucol. Am J Cardiol 1988; 62: 73B–6B

    PubMed  CAS  Google Scholar 

  49. Franceschini G, Sirtori M, Vaccarino V, et al. Mechanisms of HDL reduction after probucol: changes in HDL subfractions and increased cholesteryl ester transfer. Arteriosclerosis 1989; 9: 462–9

    PubMed  CAS  Google Scholar 

  50. Bagdate JD, Kaufman D, Ritter MC, et al. Probucol treatment in hypercholesterolemic patients: effects on lipoprotein composition, HDL particle size and cholesteryl ester transfer. Atherosclerosis 1990; 84: 145–54

    Google Scholar 

  51. McPherson R, Hogue M, Milne RW, et al. Increase in plasma cholesteryl ester transfer protein during probucol treatment. Relation to changes in high density lipoprotein composition. Arterioscler Thromb 1991; 11: 476–81

    PubMed  CAS  Google Scholar 

  52. Ku G, Doherty NS, Schmidt LF, et al. Ex vivo lipopolysaccharide-induced interleukin-1 secretion from murine peritoneal macrophages inhibited by probucol, a hypocholesterolemic agent with antioxidant properties. FASEB J 1990; 4: 1645–53

    PubMed  CAS  Google Scholar 

  53. Ferns GAA, Forster L, Stewart-Lee A, et al. Probucol inhibits mononuclear cell adhesion to vascular endothelium in the cholesterol-fed rabbit. Atherosclerosis 1993; 100: 171–81

    PubMed  CAS  Google Scholar 

  54. Bjökhem I, Henriksson-Freyschuss A, Breuer et al. The antioxidant butylated hydroxytoluene protects against atherosclerosis. Arterioscler Thromb 1991; 11: 15–22

    Google Scholar 

  55. Freyschuss A, Stiko-Rahm A, Swedenborg J, et al. Antioxidant treatment inhibits the development of intimal thickening after balloon injury of the aorta in hypercholesterolemic rabbits. J Clin Invest 1993; 91: 1282–8

    PubMed  CAS  Google Scholar 

  56. Sparrow CP, Doebber TW, Olszewski J, et al. Low density lipoprotein is protected from oxidation and the progression of atherosclerosis is slowed in cholesterol-fed rabbits by the antioxidant N, N′-diphenyl-phenylenediamine. J Clin Invest 1992; 89: 1885–91

    PubMed  CAS  Google Scholar 

  57. Kannel WB, D’Agostino RB, Belanger AJ. Update on fibrinogen as a cardiovascular risk factor. Ann Epidemiol 1992; 2: 457–66

    PubMed  CAS  Google Scholar 

  58. Ernst E. The role of fibrinogen as a cardiovascular risk factor. Atherosclerosis 1993; 100: 1–12

    PubMed  CAS  Google Scholar 

  59. Ernst E, Resch KL. Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med 1993; 118: 956–63

    PubMed  CAS  Google Scholar 

  60. Qizilbash N, Jones L, Warlow C, et al. Fibrinogen and lipid concentrations as risk factors for transient ischaemic attacks and minor ischaemic strokes. BMJ 1991; 303: 605–9

    PubMed  CAS  Google Scholar 

  61. Kannel WB, D’Agostino RB, Belanger AJ. Fibrinogen, cigarette smoking, and risk of cardiovascular disease: insights from the Framingham Study. Am Heart J 1990; 120: 672–6

    PubMed  CAS  Google Scholar 

  62. Smith EB, Thompson WD. Fibrin as a factor in atherogenesis. Thromb Res 1994; 73: 1–19

    PubMed  CAS  Google Scholar 

  63. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1994; 362: 801–9

    Google Scholar 

  64. Bini A, Fenoglio Jr JJ, Mesa-Tejada R, et al. Identification and distribution of fibrinogen, fibrin, and fibrin(ogen) degradation products in atherosclerosis: use of monoclonal antibodies. Arteriosclerosis 1989; 9: 109–21

    PubMed  CAS  Google Scholar 

  65. Naito M, Funaki C, Hayashi T, et al. Substrate-bound fibrinogen, fibrin and other cell attachment-promoting proteins as a scaffold for cultured vascular smooth muscle cells. Atherosclerosis 1992; 96: 227–34

    PubMed  CAS  Google Scholar 

  66. Naito M, Hayashi T, Kuzuya M, et al. Fibrinogen is chemotactic for vascular smooth muscle cells. FEBS Lett 1989; 247: 358–60

    PubMed  CAS  Google Scholar 

  67. Naito M, Hayashi T, Kuzuya M, et al. Effects of fibrinogen and fibrin on the migration of vascular smooth muscle cells in vitro. Atherosclerosis 1990; 83: 9–14

    PubMed  CAS  Google Scholar 

  68. Koenig W, Sund M, Lowe GDO, et al. Geographical variations in plasma viscosity and relation to coronary event rates. Lancet 1994; 344: 711–4

    PubMed  CAS  Google Scholar 

  69. Naski MC, Shafer JA. A kinetic model for the a-thrombin catalyzed conversion of plasma levels of fibrinogen to fibrin in the presence of antithrombin III. J Biol Chem 1991; 266: 13003–10

    PubMed  CAS  Google Scholar 

  70. Scrutton MC, Rossmurphy SB, Bennett GM, et al. Changes in clot deformability — a possible explanation for the epidemiological association between plasma fibrinogen concentration and myocardial infarction. Blood Coag Fibrinol 1994; 5: 719–23

    CAS  Google Scholar 

  71. Fibrinogen and cardiovascular disease. Based on the Second International Symposium on Fibrinogen and Cardiovascular Disease, held at the Royal College of Physicians, Edinburgh, Scotland, 1-2 November 1994. Eur Heart J 1995; 16 Suppl. A: 1–63

  72. van Pelt-Verkuil E, van de Ree P, Emeis JJ, et al. Defibrinogenation by Arvin reduces air-drying-induced arteriosclerosis in rat carotid artery. Thromb Haemost 1989; 61: 246–9

    PubMed  Google Scholar 

  73. Ceriello A, Pirisi M, Giacomello R, et al. Fibrinogen plasma levels as a marker of thrombin activation: new insights on the role of fibrinogen as a cardiovascular risk factor. Thromb Haemost 1994; 71: 593–5

    PubMed  CAS  Google Scholar 

  74. Dormandy JA, Gutteridge JMC, Hoare E, et al. Effect of Clofibrate on blood viscosity in intermittent claudication. BMJ 1974; 4: 259–61

    PubMed  CAS  Google Scholar 

  75. Green KG, Heady A, Oliver MF. Blood pressure, cigarette smoking and heart attack in the WHO cooperative trial of Clofibrate. Int J Epidemiol 1989; 18: 355–60

    PubMed  CAS  Google Scholar 

  76. Ernst E. Lowering the plasma fibrinogen concentration with drugs. Clin Pharmacol 1992; 11: 968–71

    CAS  Google Scholar 

  77. Zimmermann R, Ehlers W, Walter E. The effect of bezafibrate on the fibrinolytic system. Atherosclerosis 1978; 29: 477–85

    PubMed  CAS  Google Scholar 

  78. Nikort G, Bulgarelli A, Cassader M, et al. Effect of short term treatment with bezafibrate on plasma fibrinogen, fibrinopeptide A, platelet activation and blood filterability in atherosclerotic hyperfibrinogenemic patients. Atherosclerosis 1988; 71: 113–9

    Google Scholar 

  79. Winocour PH, Durrington PN, Bhatnagar D, et al. Double blind placebo-controlled study of the effects of bezafibrate on blood lipids, lipoproteins, and fibrinogen in hyperlipidaemic type I diabetes mellitus. Diabetic Med 1990; 7: 736–43

    PubMed  CAS  Google Scholar 

  80. Mathur S, Barradas MA, Mikhailidis DP, et al. The effect of a slow release formulation of bezafibrate on lipids, glucose homeostasis, platelets and fibrinogen in type II diabetics: a pilot study. Diabetes Res 1990; 14: 133–8

    PubMed  CAS  Google Scholar 

  81. Pazzucconi F, Mannucci L, Mussoni L, et al. Bezafibrate lowers plasma lipids, fibrinogen and platelet aggregability in hypertriglyceridemia. Eur J Clin Pharmacol 1992; 43: 219–23

    PubMed  CAS  Google Scholar 

  82. Specht-Leible N, Schlierf G, Lang PD, et al. Fibrinogen and bezafibrate — a pilot study in patients following percutaneous transluminal coronary angioplasty (PTCA). Clin Hemorheol 1993; 13: 679–85

    Google Scholar 

  83. Herrmann JM, Mayer EO. A long term study of the effects of Celiprolol on blood pressure and lipid-associated risk factors. Am Heart J 1988; 116: 1416–21

    PubMed  CAS  Google Scholar 

  84. Shahar E, Folsom AR, Wu KK, et al. Association of fish intake and dietary n-3 polyunsaturated fatty acids with a hypocoagulable profile. The Atherosclerosis Risk in Communities (ARIC) Study. Arterioscler Thromb 1993; 13: 1205–12

    PubMed  CAS  Google Scholar 

  85. Mudd SH, Levy HL, Skovby F. Disorders of transsulfuration. In: Scriber CR, Beaudet AL, Sly WS, et al., editors. The metabolic basis of inherited disease. New York: McGraw-Hill, 1989: 693–734

    Google Scholar 

  86. Rees MM, Rodgers GM. Homocysteinemia: association of a metabolic disorder with vascular disease and thrombosis. Thromb Res 1993; 71: 337–59

    PubMed  CAS  Google Scholar 

  87. Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria due to cystathionine-β-synthase deficiency. Am J Hum Genet 1985; 37: 1–31

    PubMed  CAS  Google Scholar 

  88. Olszewski AJ, McCully KS. Homocysteine metabolism and the oxidative modification of proteins and lipids. Free Radical Biol Med 1993; 14: 683–93

    CAS  Google Scholar 

  89. McCully KS, Ragsdale BD. Production of arteriosclerosis by homocysteinemia. Am J Pathol 1970; 61: 1–8

    PubMed  CAS  Google Scholar 

  90. Harker LA, Ross R, Slichter SJ, et al. Homocysteine-induced arteriosclerosis: the role of endothelial injury and platelet response in its genesis. J Clin Invest 1976; 58: 731–41

    PubMed  CAS  Google Scholar 

  91. Starkebaum G, Harlan JM. Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Clin Invest 1986; 77: 1370–6

    PubMed  CAS  Google Scholar 

  92. Wall RT, Harlan JM, Harker LA, et al. Homocysteine-induced endothelial cell injury in vitro: a model for the study of vascular injury. Thromb Res 1980; 18: 113–21

    PubMed  CAS  Google Scholar 

  93. Bostom AG, Jacques PF, Nadeau MR, et al. Post-methionine load hyperhomocysteinemia in persons with normal fasting total plasma homocysteine: initial results from the NHLBI Family Heart Study. Atherosclerosis 1995; 116: 147–51

    PubMed  CAS  Google Scholar 

  94. Szostak WB. Contribution of homocysteine to atherogenesis. Klin Lab 1992; 38: 10–2

    CAS  Google Scholar 

  95. Miller LT, Dow MJ, Kokkeler SC. Methionine metabolism and vitamin status in women using oral contraceptives. Am J Clin Nutr 1978; 31: 619–25

    PubMed  CAS  Google Scholar 

  96. Beaumont V, Malinow MR, Sexton G, et al. Hyperhomocyst(e)inemia, anti-estrogen antibodies, and other risk factors for thrombosis in women on oral contraceptives. Atherosclerosis 1992; 94: 147–52

    PubMed  CAS  Google Scholar 

  97. Boers GHJ, Smals AGH, Trijbels JMF, et al. Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease. N Engl J Med 1985; 313: 709–15

    PubMed  CAS  Google Scholar 

  98. Genest JJ, McNamara JR, Upson et al. Prevalence of familial hyperhomocyst(e)inemia in men with premature coronary artery disease. Arterioscler Thromb 1991; 11: 1129–36

    PubMed  Google Scholar 

  99. Clarke R, Daly L, Robinson K, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991; 324: 1149–55

    PubMed  CAS  Google Scholar 

  100. Brattström L, Israelsson Norrving et al. Impaired homocysteine metabolism in early-onset cerebral and peripheral occlusive arterial disease: effects of pyridoxine and folic acid treatment. Atherosclerosis 1990; 81: 51–60

    PubMed  Google Scholar 

  101. Franken DG, Boers GHJ, Blom HJ, et al. Treatment of mild hyperhomocysteinemia in vascular disease patients. Arterioscler Thromb 1994; 14: 465–70

    PubMed  CAS  Google Scholar 

  102. Colditz GA, Willett WC, Stampfer MJ, et al. Menopause and the risk of coronary heart disease in women. N Engl J Med 1987; 316: 1105–10

    PubMed  CAS  Google Scholar 

  103. Witteman JCM, Grobbee DE, Kok FJ, et al. Increased risk of atherosclerosis in women after the menopause. BMJ 1989; 298: 642–4

    PubMed  CAS  Google Scholar 

  104. Stampfer MJ, Willett WC, Colditz GA, et al. A prospective study of postmenopausal estrogen therapy and coronary heart disease. N Engl J Med 1985; 313: 1044–9

    PubMed  CAS  Google Scholar 

  105. Wilson PWF, Garrison RJ, Castelli WP. Postmenopausal estrogen use, cigarette smoking, and cardiovascular morbidity in women over 50: the Framingham Study. N Engl J Med 1985; 313: 1038–43

    PubMed  CAS  Google Scholar 

  106. Psaty BM, Heckbert SR, Atkins D, et al. A review of the association of estrogens and progestins with cardiovascular disease. Arch Intern Med 1993; 153: 1421–7

    PubMed  CAS  Google Scholar 

  107. Bush TL, Barrett-Conor E. Noncontraceptive estrogen use and cardiovascular disease. Epidemiol Rev 1985; 7: 89–104

    PubMed  CAS  Google Scholar 

  108. Bush TL, Barrett-Conor E, Cowan LD, et al. Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study. Circulation 1987; 75: 1102–9

    PubMed  CAS  Google Scholar 

  109. Rosenberg L, Palmer JR, Shapiro S. A case-control study of myocardial infarction in relation to use of estrogen supplements. Am J Epidemiol 1993; 137: 54–63

    PubMed  CAS  Google Scholar 

  110. Windier E, Kovanen Y, Chao S, et al. The estradiol stimulated lipoprotein receptor of rat liver: a binding site that mediates the uptake of rat lipoproteins containing apoprotein and E. J Biol Chem 1980; 255: 10464–71

    Google Scholar 

  111. Ma PT, Yamamoto T, Goldstein JL, et al. Increased mRNA for low density lipoprotein receptor in liver of rabbits treated with 17-alpha ethinyl estradiol. Proc Natl Acad Sci USA 1986; 83: 792–6

    PubMed  CAS  Google Scholar 

  112. Hazzard WR. The sex differential in longevity. In: Hazzard WR, Andres R, Bierman EL, et al., editors. Principles of geriatric medicine and gerontology. 2nd ed. New York: McGraw-Hill, 1990: 37–47

    Google Scholar 

  113. Philips GB. Evidence for hyperestrogenemia as a risk factor for myocardial infarction in men. Lancet 1976; 2: 14–8

    Google Scholar 

  114. Veterans Administration Cooperative Urological Research Group. Treatment and survival of patients with cancer of the prostate. Surg Gynecol Obstetr 1967; 124: 1011–7

    Google Scholar 

  115. Coronary Drug Project Research Group. The coronary drug project: initial findings leading to modifications of research protocol. JAMA 1970; 214: 1303–13

    Google Scholar 

  116. Stampfer MJ, Colditz GA, Wilett WC. Postmenopausal estrogen therapy and cardiovascular disease. N Engl J Med 1991; 325: 756–62

    PubMed  CAS  Google Scholar 

  117. Soma MR, Osnago-Gadda I, Paoletti R, et al. The lowering of lipoprotein [a] induced by estrogen plus progesterone replacement therapy in postmenopausal women. Arch Intern Med 1993; 153: 1462–8

    PubMed  CAS  Google Scholar 

  118. Nabulsi AA, Aaron White A, et al. Association of hormonereplacement therapy with various cardiovascular risk factors in postmenopausal women. N Engl J Med 1993; 328: 1069–75

    PubMed  CAS  Google Scholar 

  119. Gruchow HW, Anderson AJ, Barboriak JJ, et al. Postmenopausal use of estrogen and occlusion of coronary arteries. Am Heart J 1988; 115: 854–963

    Google Scholar 

  120. Sullivan JM, Vander-Zwang R, Lemp GF. Postmenopausal estrogen use and coronary atherosclerosis. Ann Intern Med 1988; 108: 358–63

    PubMed  CAS  Google Scholar 

  121. Adams MR, Clarkson Kaplan JR, et al. Ovarian secretions and atherosclerosis. In: Naftolin F, Gutmann JN, DeChemey AH, et al., editors. Ovarian secretions and cardiovascular and neurological function. New York: Raven, 1990: 151–9

    Google Scholar 

  122. Magness RR, Rosenfeld CR. Local and systemic estradiol-17beta: effects on uterine and systemic vasodilation. Am J Physiol 1989; 256: E536–42

    PubMed  CAS  Google Scholar 

  123. Williams JK, Adams MR, Klopfenstein HS. Estrogen modulates responses of atherosclerotic coronary arteries. Circ Res 1990; 81: 1680–7

    CAS  Google Scholar 

  124. Hayashi T, Fukuto JM, Ignarro LJ, et al. Basal release of nitric oxide from aortic rings is greater in female rabbits than in male rabbits: implications for atherosclerosis. Proc Natl Acad Sci USA 1992; 89: 11259–62

    PubMed  CAS  Google Scholar 

  125. Collins P, Rosano GM, Jiang et al. Cardiovascular protection by oestrogen — a calcium antagonist effect? Lancet 1993; 341: 1264–5

    PubMed  CAS  Google Scholar 

  126. Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987; 327: 524–6

    PubMed  CAS  Google Scholar 

  127. Radomski MW, Palmer RMJ, Moncada S. Comparative pharmacology of endothelium-derived relaxing factor, nitric oxide, and prostacyclin in platelets. Br J Pharmacol 1987; 92: 181–7

    PubMed  CAS  Google Scholar 

  128. Bath PMW, Hassall DG, Gladwin A-M, et al. Nitric oxide and prostacyclin: divergence of inhibitory effects on monocyte Chemotaxis and adhesion to endothelium in vitro. Arterioscler Thromb 1991; 11: 254–60

    PubMed  CAS  Google Scholar 

  129. Tsao PS, McEvoy LM, Drexler H, et al. Enhanced endothelial adhesiveness in hypercholesterolemia is attenuated by L-arginine. Circulation 1994; 89: 2176–82

    PubMed  CAS  Google Scholar 

  130. Radomski MW, Palmer RMJ, Moncada S. The anti-aggregating properties of vascular endothelium; interactions between prostacyclin and nitric oxide. Br J Pharmacol 1987; 92: 639–46

    PubMed  CAS  Google Scholar 

  131. Xiao J, Pang PKT. Does a general alteration in nitric oxide synthesis system occur in spontaneously hypertensive rats? Am J Physiol 1994; 266: H272–8

    PubMed  CAS  Google Scholar 

  132. Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 1989; 83: 1774–7

    PubMed  CAS  Google Scholar 

  133. Verbeuren TJ, Jordaens FH, Zonnekeyn LL, et al. Effect of hypercholesterolemia on vascular reactivity in the rabbit: I. Endothelium-dependent and endothelium-independent contractions and relaxations in isolated arteries of control and hypercholesterolemic rabbits. Circ Res 1986; 58: 552–64

    PubMed  CAS  Google Scholar 

  134. Hayashi T, Naito M, Ishikawa F, et al. β-Migrating very low density lipoprotein attenuates endothelium-dependent relaxation in rabbit atherosclerotic aortas. Blood Vessels 1989; 26: 290–9

    PubMed  CAS  Google Scholar 

  135. Hayashi T, Ishikawa T, Naito M, et al. Low level hyperlipidemia impairs endothelium-dependent relaxation of porcine coronary arteries by two mechanisms: functional change in endothelium and impairment of endothelium-dependent relaxation by two mediators. Atherosclerosis 1991; 87: 23–38

    PubMed  CAS  Google Scholar 

  136. Cooke JP, Singer AH, Tsao P, et al. Anti-atherogenic effects of L-arginine in the hypercholesterolemic rabbit. J Clin Invest 1992; 90: 1168–72

    PubMed  CAS  Google Scholar 

  137. Naruse K, Shimizu K, Muramatsu M, et al. Prostaglandin H2does not contribute to impaired endothelium-dependent relaxation and long-term inhibition of nitric oxide synthesis promotes atherosclerosis in hypercholesterolemic rabbit thoracic aorta. Arterioscler Thromb 1994; 14: 746–52

    PubMed  CAS  Google Scholar 

  138. Cayatte AJ, Palacino JJ, Horten et al. Chronic inhibition of nitric oxide production accelerates neointima formation and impairs endothelial function in hypercholesterolemic rabbits. Arterioscler Thromb 1994; 14: 753–9

    PubMed  CAS  Google Scholar 

  139. Zeiher AM, Schray-Utz B, Busse R. Nitric oxide modulates monocyte chemoattractant protein 1 in human endothelial cells: implications for pathogenesis of atherosclerosis [abstract]. Circulation 1993; 88: 1367

    Google Scholar 

  140. Clancy RM, Leszczynska-Piziak J, Abramson RB. Nitric oxide, an endothelial cell relaxation factor, inhibits superoxide anion production via a direct action on NADPH oxidase. J Clin Invest 1992; 90: 1116–21

    PubMed  CAS  Google Scholar 

  141. Mao S, Yates M, Lambart L, et al. Nitric oxide protects against the oxidative modification of low density lipoprotein by macrophages [abstract]. FASEB J 1992; 6: A1030

    Google Scholar 

  142. Hogg N, Kalyanaraman B, Joseph J, et al. Inhibition of low-density lipoprotein oxidation by nitric oxide: potential role in atherogenesis. FEBS Lett 1993; 334: 170–4

    PubMed  CAS  Google Scholar 

  143. Beckman JS, Beckman TW, Chen J, et al. Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 1990; 87: 1620–4

    PubMed  CAS  Google Scholar 

  144. Zhang J, Snyder SH. Nitric oxide stimulated auto-ADP-ribosylation of glyceraldehyde-3-phosphate dehydrogenase. Proc Natl Acad Sci USA 1992; 89: 9382–5

    PubMed  CAS  Google Scholar 

  145. Drapier JC, Hibbs Jr JB. Murine cytotoxic activated macrophages inhibit aconitase in tumor cells. J Clin Invest 1986; 78: 790–7

    PubMed  CAS  Google Scholar 

  146. Leproivre M, Chenais B, Yapo A, et al. Alterations of ribonucleotide reductase activity following induction of nitrite-generating pathway in adenocarcinoma cells. J Biol Chem 1990; 265: 14143–9

    Google Scholar 

  147. Zhang J, Dawson VL, Dawson TM, et al. Nitric oxide activation of poly(ADP-ribose) synthetase in neurotoxicity. Science 1994; 263: 687–9

    PubMed  CAS  Google Scholar 

  148. Langrehr JM, Hoffman RA, Lancaster Jr JR, et al. Nitric oxide — a new endogenous immunomodulator. Transplantation 1993; 55: 1205–12

    PubMed  CAS  Google Scholar 

  149. Warren JB, Pons F, Brady AJB. Nitric oxide biology: implications for cardiovascular therapeutics. Cardiovasc Res 1994; 28: 25–30

    PubMed  CAS  Google Scholar 

  150. Cleland JGF, Krikler DM. Modification of atherosclerosis by agents that do not lower cholesterol. Br Heart J 1993; 69: S54–62

    PubMed  CAS  Google Scholar 

  151. Naito M, Kuzuya F. Effects of calcium antagonists and other hypertensive agents on experimental atherosclerosis: a review. J Clin Biochem Nutr 1993; 15: 77–90

    CAS  Google Scholar 

  152. Raines EW, Ross R. Smooth muscle cells and the pathogenesis of the lesions of atherosclerosis. Br Heart J 1993; 69: S30–7

    PubMed  CAS  Google Scholar 

  153. Liu AC, Lawn RM. Vascular interactions of lipoprotein (a). Curr Opin Lipidol 1994; 5: 269–73

    PubMed  CAS  Google Scholar 

  154. Dahlén GH. Lp(a) lipoprotein in cardiovascular disease. Atherosclerosis 1994; 108: 111–26

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Geriatrics, Nagoya University School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466, Japan

    Michitaka Naito, Toshio Hayashi & Akihisa Iguchi

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  1. Michitaka Naito
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  2. Toshio Hayashi
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  3. Akihisa Iguchi
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Naito, M., Hayashi, T. & Iguchi, A. New Approaches to the Prevention of Atherosclerosis. Drugs 50, 440–453 (1995). https://doi.org/10.2165/00003495-199550030-00003

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