Skip to main content
SpringerLink
Log in

Did the antioxidant trials fail to validate the oxidation hypothesis?

  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

Most clinical trials on antioxidants using vitamin E or β-carotene have failed to note any significant change in cardiovascular endpoints. The results of these studies have been interpreted as a setback for the oxidation hypothesis. An analysis of the hypothesis and the trials, however, points out major misconceptions about the hypothesis and unjustified outcome expectations. Wrong selection of patient population, endpoints that are incompatible with the hypothesis, poor choice of antioxidants, and lack of inclusion of biochemical markers of oxidative stress and markers of vascular response are some of the contributors to the “failure” of these trials.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Hessler JR, Robertson AL Jr, Chisolm GM: LDL-induced cytotoxicity and its inhibition by HDL in human vascular smooth muscle and endothelial cells in culture. Atherosclerosis. 1979, 32:213–229.

    Article  PubMed  CAS  Google Scholar 

  2. Henriksen T, Evensen SA, Carlander B: Injury to cultured endothelial cells induced by low density lipoproteins: protection by high density lipoproteins. Scand J Clin Lab Invest 1979, 39:369–735.

    PubMed  CAS  Google Scholar 

  3. Quinn MT, Parthasarathy S, Fong LG, Steinberg D: Oxidatively modified low density lipoproteins: a potential role in recruitment and retention of monocyte/macrophages during atherogenesis. Proc Natl Acad Sci U S A 1987, 84:2995–2998.

    Article  PubMed  CAS  Google Scholar 

  4. Steinberg D, Parthasarathy S, Carew TE, et al.: Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989, 320:915–924.

    Article  PubMed  CAS  Google Scholar 

  5. Fogelman AM, Van Lenten BJ, Warden C, et al.: Macrophage lipoprotein receptors. J Cell Sci Suppl 1988, 9:135–149.

    PubMed  CAS  Google Scholar 

  6. Parthasarathy S, Merchant NK, Penumetcha M, Santanam N: Oxidation and cardiovascular disease—potential role of oxidants in inducing antioxidant defense enzymes. J Nucl Cardiol 2001, 8:379–389.

    Article  PubMed  CAS  Google Scholar 

  7. Berliner J, Leitinger N, Watson A, et al.: Oxidized lipids in atherogenesis: formation, destruction and action. Thromb Haemost 1997, 78:195–199.

    PubMed  CAS  Google Scholar 

  8. Haberland ME, Fong D, Cheng L: Malondialdehyde-altered protein occurs in atheroma of Watanabe heritable hyperlipidemic rabbits. Science 1988, 241:215–218.

    Article  PubMed  CAS  Google Scholar 

  9. Palinski W, Yla-Herttuala S, Rosenfeld ME, et al.: Antisera and monoclonal antibodies specific for epitopes generated during oxidative modification of low density lipoprotein. Arteriosclerosis 1990, 10:325–335.

    PubMed  CAS  Google Scholar 

  10. Chen Q, Esterbauer H, Jurgens G: Studies on epitopes on low-density lipoprotein modified by 4- hydroxynonenal. Biochemical characterization and determination. Biochem J 1992, 288:249–254.

    PubMed  CAS  Google Scholar 

  11. Chisolm GM: Antioxidants and atherosclerosis: a current assessment. Clin Cardiol 1991, 14:125–30.

    Google Scholar 

  12. Parthasarathy S, Santanam N, Ramachandran S, Meilhac O: Oxidants and antioxidants in atherogenesis—an appraisal. J Lipid Res 1999, 40:2143–2157.

    PubMed  CAS  Google Scholar 

  13. Zhang SH, Reddick RL, Avdievich E, et al.: Paradoxical enhancement of atherosclerosis by probucol treatment in apolipoprotein E-deficient mice. J Clin Invest 1997, 99:2858–2866.

    PubMed  CAS  Google Scholar 

  14. Napoli C, D’Armiento FP, Mancini FP, et al.: Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions. J Clin Invest 1997, 100:2680–2690.

    PubMed  CAS  Google Scholar 

  15. Owens GK, Vernon SM, Madsen CS: Molecular regulation of smooth muscle cell differentiation. J Hyperten 1996, 14(suppl):S55–64.

    Article  CAS  Google Scholar 

  16. Owens RT, Wagner WD: Proteoglycans produced by cholesterol-enriched macrophages bind plasma low density lipoprotein. Atherosclerosis 1991, 91:229–240.

    Article  PubMed  CAS  Google Scholar 

  17. Hariri RJ, Hajjar DP, Coletti D, et al.: Aging and arteriosclerosis. Cell cycle kinetics of young and old arterial smooth muscle cells. Am J Pathol 1988, 131:132–136.

    PubMed  CAS  Google Scholar 

  18. Libby P, Geng YG, Aikawa M, et al.: Macrophages and atherosclerotic plaque stability. Curr Opin Lipidol 1996, 7:330–335.

    PubMed  CAS  Google Scholar 

  19. Hansson GK: Cell-mediated immunity in atherosclerosis. Curr Opin Lipidol 1997, 8:301–311.

    PubMed  CAS  Google Scholar 

  20. Navab M, Fogelman AM, Berliner JA, et al.: Pathogenesis of atherosclerosis. Am J Cardiol 1995, 76:18C-23C.

    Article  PubMed  CAS  Google Scholar 

  21. Khan BV, Parthasarathy S, Alexander RW, Medford RM: Modified low density lipoprotein and its constituents augment cytokine-activated vascular cell adhesion molecule-1 gene expression in human vascular endothelial cells. J Clin Invest 1995, 95:1262–1270.

    PubMed  CAS  Google Scholar 

  22. Cushing SD, Berliner JA, Valente VJ, et al.: Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc Natl Acad Sci U S A 1990, 87:5134–5138.

    Article  PubMed  CAS  Google Scholar 

  23. Frostegard J, Nilsson J, Haegerstrand A, et al.: Oxidized low density lipoprotein induces differentiation and adhesion of human monocytes and the monocytic cell line U937. Proc Natl Acad Sci U S A 1990, 87:904–908.

    Article  PubMed  CAS  Google Scholar 

  24. Marui N, Offermann MK, Swerlick R, et al.: Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells. J Clin Invest 1993, 92:1866–1874.

    PubMed  CAS  Google Scholar 

  25. Parhami F, Fang ZT, Fogelman AM, et al.: Minimally modified low density lipoprotein-induced inflammatory responses in endothelial cells are mediated by cyclic adenosine monophosphate. J Clin Invest 1993, 92:471–478.

    Article  PubMed  CAS  Google Scholar 

  26. Salonen JT, Yla-Herttuala S, Yamamoto R, et al.: Autoantibody against oxidised LDL and progression of carotid atherosclerosis. Lancet 1992, 339:883–887.

    Article  PubMed  CAS  Google Scholar 

  27. De Caterina R, Basta G, Lazzerini G, et al.: Soluble vascular cell adhesion molecule-1 as a biohumoral correlate of atherosclerosis. Arterioscler Thromb Vasc Biol 1997, 17:2646–2654.

    PubMed  Google Scholar 

  28. Dekkers JC, van Doornen LJ, Kemper HC: The role of antioxidant vitamins and enzymes in the prevention of exercise-induced muscle damage. Sports Med 1996, 21:213–238.

    PubMed  CAS  Google Scholar 

  29. Marz W, Wieland H: HMG-CoA reductase inhibition: anti-inflammatory effects beyond lipid lowering? Herz 2000, 25:117–125.

    Article  PubMed  CAS  Google Scholar 

  30. Navalkar S, Parthasarathy S, Santanam N, Khan BV: Irbesartan, an angiotensin type 1 receptor inhibitor, regulates markers of inflammation in patients with premature atherosclerosis. J Am Coll Cardiol 2001, 37:440–444.

    Article  PubMed  CAS  Google Scholar 

  31. Santanam N, Jonas C, Murphy AA, Parthasarathy S: Vitamin E supplementation decreases autoantibodies to oxidized-lipid protein complexes. J Medicinal Food 1999, 1:247–251.

    Google Scholar 

  32. Schwenke DC: Antioxidants, dietary fat saturation, lipoprotein oxidation and atherogenesis. Nutrition 1996, 12:377–379.

    Article  PubMed  CAS  Google Scholar 

  33. Meilhac O, Zhou M, Santanam N, Parthasarathy S: Lipid peroxides induce expression of catalase in cultured vascular cells. J Lipid Res 2000, 41:1205–1213.

    PubMed  CAS  Google Scholar 

  34. Azzi A, Boscoboinik D, Clement S, et al.: Vitamin E mediated response of smooth muscle cell to oxidant stress. Diabetes Res Clin Practice 1999, 45:191–198.

    Article  CAS  Google Scholar 

  35. Azen SP, Qian D, Mack WJ, et al.: Effect of supplementary antioxidant vitamin intake on carotid arterial wall intima-media thickness in a controlled clinical trial of cholesterol lowering. Circulation. 1996, 94:2369–2372.

    PubMed  CAS  Google Scholar 

  36. Weis JR, Pitas RE, Wilson BD, Rodgers GM: Oxidized low-density lipoprotein increases cultured human endothelial cell tissue factor activity and reduces protein C activation. Faseb J 1991, 5:2459–2465.

    PubMed  CAS  Google Scholar 

  37. Drake TA, Hannani K, Fei HH, et al.: Minimally oxidized low-density lipoprotein induces tissue factor expression in cultured human endothelial cells. Am J Pathol 1991, 138:601–607.

    PubMed  CAS  Google Scholar 

  38. Rajagopalan S, Meng XP, Ramasamy S, et al.: Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. Implications for atherosclerotic plaque stability. J Clin Invest 1996, 98:2572–2579.

    PubMed  CAS  Google Scholar 

  39. Aviram M: Modified forms of low density lipoprotein affect platelet aggregation in vitro. Thromb Res 1989, 53:561–567.

    Article  PubMed  CAS  Google Scholar 

  40. Dagenais GR, Marchioli R, Yusuf S, Tognoni G: Beta-carotene, vitamin C, and vitamin E and cardiovascular diseases. Curr Cardiol Rep 2000, 2:293–299.

    Article  PubMed  CAS  Google Scholar 

  41. Stocker A, Azzi A: Tocopherol-binding proteins: their function and physiological significance. Antioxid Redox Signal 2000, 2:397–404.

    Article  PubMed  CAS  Google Scholar 

  42. Steinberg D: Antioxidants in the prevention of human atherosclerosis. Summary of the proceedings of a National Heart, Lung, and Blood Institute Workshop: September 5–6, 1991, Bethesda, Maryland. Circulation 1992, 85:2337–2344.

    PubMed  CAS  Google Scholar 

  43. Berliner JA, Territo MC, Sevanian A, et al.: Minimally modified low density lipoprotein stimulates monocyte endothelial interactions. J Clin Invest 1990, 85:1260–1266.

    PubMed  CAS  Google Scholar 

  44. Smith JD, Trogan E, Ginsberg M, et al.: Decreased atherosclerosis in mice deficient in both macrophage colony- stimulating factor (op) and apolipoprotein E. Proc Natl Acad Sci U S A 1995, 92:8264–8268.

    Article  PubMed  CAS  Google Scholar 

  45. Henriksen T, Mahoney EM, Steinberg D: Enhanced macrophage degradation of biologically modified low density lipoprotein. Arteriosclerosis 1983, 3:149–159.

    PubMed  CAS  Google Scholar 

  46. Nakao J, Ooyama T, Ito H, et al.: Comparative effect of lipoxygenase products of arachidonic acid on rat aortic smooth muscle cell migration. Atherosclerosis 1982, 44:339–342.

    Article  PubMed  CAS  Google Scholar 

  47. Marcus AJ, Hajjar DP: Vascular transcellular signaling. J Lipid Res 1993, 34:2017–2031.

    PubMed  CAS  Google Scholar 

  48. Schwartz CJ, Valente AJ, Sprague EA, et al.: The pathogenesis of atherosclerosis: an overview. Clin Cardiol 1991, 14:11–16.

    Google Scholar 

  49. Shi H, Severs NJ, Robenek H: Effects of calcium on the migration and recruitment of macrophages and macrophage-derived foam cells. Faseb J 1996, 10:491–501.

    PubMed  CAS  Google Scholar 

  50. Mitchinson MJ, Hardwick SJ, Bennett MR: Cell death in atherosclerotic plaques. Curr Opin Lipidol. 1996, 7:324–329.

    PubMed  CAS  Google Scholar 

  51. Holvoet P, Collen D: Thrombosis and atherosclerosis. Curr Opin Lipidol 1997, 8:320–328.

    Article  PubMed  CAS  Google Scholar 

  52. Petit L, Lesnik P, Dachet C, et al.: Tissue factor pathway inhibitor is expressed by human monocyte-derived macrophages: relationship to tissue factor induction by cholesterol and oxidized LDL. Arterioscler Thromb Vasc Biol 1999, 19:309–315.

    PubMed  CAS  Google Scholar 

  53. Blot WJ, Li JY, Taylor PR, et al.: Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 1993, 85:1483–1492.

    Article  PubMed  CAS  Google Scholar 

  54. Rapola JM, Virtamo J, Ripatti S, et al.: Randomised trial of alpha-tocopherol and beta-carotene supplements on incidence of major coronary events in men with previous myocardial infraction. Lancet 1997, 349:1715–1720.

    Article  PubMed  CAS  Google Scholar 

  55. Greenberg ER, Baron JA, Karagas MR, et al.: Mortality associated with low plasma concentration of beta carotene and the effect of oral supplementation. JAMA 1996, 275:699–703.

    Article  PubMed  CAS  Google Scholar 

  56. Hennekens CH, Buring JE, Manson JE, et al.: Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med. 1996, 334:1145–1149.

    Article  PubMed  CAS  Google Scholar 

  57. Stephens NG, Parsons A, Schofield PM, et al.: Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996, 347:781–786.

    Article  PubMed  CAS  Google Scholar 

  58. Omenn GS, Goodman GE, Thornquist MD, et al.: Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996, 334:1150–1155.

    Article  PubMed  CAS  Google Scholar 

  59. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico.Lancet 1999, 354:447–455.

  60. Yusuf S: Effect of ACE inhibition and Vitamin E an outcome in chronic CAD: HOPE (Heart Outcomes Prevention Evaluation). 71st Scientific Meeting American Heart Association. 1999.

  61. Miller ER, Appel LJ, Levander OA, et al.: The effect of antioxidant vitamin supplementation on traditional cardiovascular risk factors. J Cardiovasc Risk 1997, 4:19–24.

    Article  PubMed  Google Scholar 

  62. Nyyssonen K, Porkkala E, Salonen R, et al.: Increase in oxidation resistance of atherogenic serum lipoproteins following antioxidant supplementation: a randomized double-blind placebo-controlled clinical trial. Eur J Clin Nutr 1994, 48:633–642.

    PubMed  CAS  Google Scholar 

  63. Kaikkonen J, Nyyssonen K, Tomasi A, et al.: Antioxidative efficacy of parallel and combined supplementation with coenzyme Q10 and d-alpha-tocopherol in mildly hypercholesterolemic subjects: a randomized placebo-controlled clinical study. Free Radic Res 2000, 33:329–340.

    Article  PubMed  CAS  Google Scholar 

  64. Regnstrom J, Walldius G, Nilsson S, et al.: The effect of probucol on low density lipoprotein oxidation and femoral atherosclerosis. Atherosclerosis 1996, 125:217–229.

    PubMed  CAS  Google Scholar 

  65. Seljeflot I, Arnesen H, Brude IR, et al.: Effects of omega-3 fatty acids and/or antioxidants on endothelial cell markers. Eur J Clin Invest 1998, 28:629–635.

    Article  PubMed  CAS  Google Scholar 

  66. Koh KK, Blum A, Hathaway L, et al.: Vascular effects of estrogen and vitamin E therapies in postmenopausal women. Circulation 1999, 100:1851–1857.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gynecology and Obstetrics, Emory University, 1639 Pierce Drive, #4300 WMB, 30322, Atlanta, GA, USA

    Sampath Parthasarathy PhD, Nadya Khan-Merchant MPH, Meera Penumetcha RD, Bobby V. Khan MD, PhD & Nalini Santanam PhD

Authors
  1. Sampath Parthasarathy PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nadya Khan-Merchant MPH
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Meera Penumetcha RD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bobby V. Khan MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nalini Santanam PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Parthasarathy, S., Khan-Merchant, N., Penumetcha, M. et al. Did the antioxidant trials fail to validate the oxidation hypothesis?. Curr Atheroscler Rep 3, 392–398 (2001). https://doi.org/10.1007/s11883-001-0077-9

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11883-001-0077-9

Keywords

Search

Navigation