Oxidized Low-Density Lipoprotein

  • Sampath Parthasarathy
  • Achuthan Raghavamenon
  • Mahdi Omar Garelnabi
  • Nalini Santanam
Part of the Methods in Molecular Biology book series (MIMB, volume 610)


Oxidized low-density lipoprotein (Ox-LDL) has been studied for over 25 years. Numerous pro- and anti-atherogenic properties have been attributed to Ox-LDL. Yet, Ox-LDL has neither been defined nor characterized, as its components and composition change depending on its source, method of preparation, storage, and use. It contains unoxidized and oxidized fatty acid derivatives both in the ester and free forms, their decomposition products, cholesterol and its oxidized products, proteins with oxidized amino acids and cross-links, and polypeptides with varying extents of covalent modification with lipid oxidation products, and many others. It seems to exist in vivo in some form not yet fully characterized. Until its pathophysiological significance, and how it is generated in vivo are determined, the nature of its true identity will be only of classical interest. In this review, its components, their biological actions and methods of preparation will be discussed.

Key words

Atherosclerosis oxidative stress lipid peroxides antioxidants aldehydes 



This work was supported by funding from National Institutes of Health, HL-069038 and HL-74239 (SP) and HL74239 (NS).


  1. 1.
    Steinbrecher, U.P., Parthasarathy, S., Leake, D.S., Witztum, J.L., and Steinberg, D. (1984) Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. Proc. Natl. Acad. Sci. USA 81, 3883–3887.PubMedCrossRefGoogle Scholar
  2. 2.
    Quinn, M.T., Parthasarathy, S., Fong, L.G., and Steinberg, D. (1987) Oxidatively modified low density lipoproteins: a potential role in recruitment and retention of monocyte/macrophages during atherogenesis. Proc. Natl. Acad. Sci. USA 84, 2995–2998.PubMedCrossRefGoogle Scholar
  3. 3.
    Steinberg, D., Parthasarathy, S., Carew, T.E., Khoo, J.C., and Witztum, J.L. (1989) Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity [see comments]. N. Engl. J. Med. 320, 915–924.PubMedCrossRefGoogle Scholar
  4. 4.
    Parthasarathy, S., Quinn, M.T., and Steinberg, D. (1988) Is oxidized low density lipoprotein involved in the recruitment and retention of monocyte/macrophages in the artery wall during the initiation of atherosclerosis? Basic Life Sci. 49, 375–380.PubMedGoogle Scholar
  5. 5.
    Fong, L.G., Parthasarathy, S., Witztum, J.L., and Steinberg, D. (1987) Nonenzymatic oxidative cleavage of peptide bonds in apoprotein B-100. J. Lipid Res. 28, 1466–1477.PubMedGoogle Scholar
  6. 6.
    Fruebis, J., Parthasarathy, S., and Steinberg, D. (1992) Evidence for a concerted reaction between lipid hydroperoxides and polypeptides. Proc. Natl. Acad. Sci. USA 89, 10588–10592.PubMedCrossRefGoogle Scholar
  7. 7.
    Parthasarathy, S., Quinn, M.T., Schwenke, D.C., Carew, T.E., and Steinberg, D. (1989) Oxidative modification of beta-very low density lipoprotein. Potential role in monocyte recruitment and foam cell formation. Arteriosclerosis 9, 398–404.PubMedGoogle Scholar
  8. 8.
    de Rijke, Y.B., Hessels, E.M., and van Berkel, T.J. (1992) Recognition sites on rat liver cells for oxidatively modified beta-very low density lipoproteins. Arterioscler. Thromb. 12, 41–49.PubMedGoogle Scholar
  9. 9.
    Bowry, V.W., Stanley, K.K., and Stocker, R. (1992) High density lipoprotein is the major carrier of lipid hydroperoxides in human blood plasma from fasting donors. Proc. Natl. Acad. Sci. USA 89, 10316–10320.PubMedCrossRefGoogle Scholar
  10. 10.
    Bradamante, S., Barenghi, L., Giudici, G.A., and Vergani, C. (1992) Free radicals promote modifications in plasma high-density lipoprotein: nuclear magnetic resonance analysis. Free Radic. Biol. Med. 12, 193–203.PubMedCrossRefGoogle Scholar
  11. 11.
    Bonnefont-Rousselot, D., Khalil, A., Delattre, J., Jore, D., and Gardes-Albert, M. (1997) Oxidation of human high-density lipoproteins by OH and OH/O(-)2 free radicals. Radiat. Res. 147, 721–728.PubMedCrossRefGoogle Scholar
  12. 12.
    Greilberger, J. and Jurgens, G. (1998) Oxidation of high-density lipoprotein HDL3 leads to exposure of apo-AI and apo-AII epitopes and to formation of aldehyde protein adducts, and influences binding of oxidized low-density lipoprotein to type I and type III collagen in vitro. Biochem. J. 331, 185–191.PubMedGoogle Scholar
  13. 13.
    Bergt, C., Oram, J.F., and Heinecke, J.W. (2003) Oxidized HDL: the paradox-idation of lipoproteins. Arterioscler. Thromb. Vasc. Biol. 23, 1488–1490.PubMedCrossRefGoogle Scholar
  14. 14.
    Asztalos, B.F. (2004) High-density lipoprotein metabolism and progression of atherosclerosis: new insights from the HDL Atherosclerosis Treatment Study. Curr. Opin. Cardiol. 19, 385–391.PubMedCrossRefGoogle Scholar
  15. 15.
    Navab, M., Ananthramaiah, G.M., Reddy, S.T., Van Lenten, B.J., Ansell, B.J., Fonarow, G.C., Vahabzadeh, K., Hama, S., Hough, G., Kamranpour, N., et al. (2004) The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL. J. Lipid Res. 45, 993–1007.PubMedCrossRefGoogle Scholar
  16. 16.
    Stojanovic, N., Krilov, D., and Herak, J.N. (2006) Slow oxidation of high density lipoproteins as studied by EPR spectroscopy. Free Radic. Res. 40, 135–140.PubMedCrossRefGoogle Scholar
  17. 17.
    Malle, E., Marsche, G., Panzenboeck, U., and Sattler, W. (2006) Myeloperoxidase-mediated oxidation of high-density lipoproteins: fingerprints of newly recognized potential proatherogenic lipoproteins. Arch. Biochem. Biophys. 445, 245–255.PubMedCrossRefGoogle Scholar
  18. 18.
    Ferretti, G., Bacchetti, T., Negre-Salvayre, A., Salvayre, R., Dousset, N., and Curatola, G. (2006) Structural modifications of HDL and functional consequences. Atherosclerosis 184, 1–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Kervinen, K., Horkko, S., Beltz, W.F., and Kesaniemi, A. (1995) Modification of VLDL apoprotein B by acetaldehyde alters apoprotein B metabolism. Alcohol 12, 189–194.PubMedCrossRefGoogle Scholar
  20. 20.
    Nagano, Y., Arai, H., and Kita, T. (1991) High density lipoprotein loses its effect to stimulate efflux of cholesterol from foam cells after oxidative modification. Proc. Natl. Acad. Sci. USA 88, 6457–6461.PubMedCrossRefGoogle Scholar
  21. 21.
    Ghiselli, G., Giorgini, L., Gelati, M., and Musanti, R. (1992) Oxidatively modified HDLs are potent inhibitors of cholesterol biosynthesis in human skin fibroblasts. Arterioscler. Thromb. 12, 929–935.PubMedGoogle Scholar
  22. 22.
    Van Lenten, B.J., Wagner, A.C., Nayak, D.P., Hama, S., Navab, M., and Fogelman, A.M. (2001) High-density lipoprotein loses its anti-inflammatory properties during acute influenza a infection. Circulation 103, 2283–2288.PubMedGoogle Scholar
  23. 23.
    Jaouad, L., Milochevitch, C., and Khalil, A. (2003) PON1 paraoxonase activity is reduced during HDL oxidation and is an indicator of HDL antioxidant capacity. Free Radic. Res. 37, 77–83.PubMedCrossRefGoogle Scholar
  24. 24.
    Parthasarathy, S. (1994) Modified Lipoproteins in the Pathogenesis of Atherosclerosis. R.G. Landes Co., Austin, TX, 152 pp.Google Scholar
  25. 25.
    Lada, A.T. and Rudel, L.L. (2004) Associations of low density lipoprotein particle composition with atherogenicity. Curr. Opin. Lipidol. 15, 19–24.PubMedCrossRefGoogle Scholar
  26. 26.
    Moreno, J.J. and Mitjavila, M.T. (2003) The degree of unsaturation of dietary fatty acids and the development of atherosclerosis (review). J. Nutr. Biochem. 14, 182–195.PubMedCrossRefGoogle Scholar
  27. 27.
    Kratz, M., Cullen, P., Kannenberg, F., Kassner, A., Fobker, M., Abuja, P.M., Assmann, G., and Wahrburg, U. (2002) Effects of dietary fatty acids on the composition and oxidizability of low-density lipoprotein. Eur. J. Clin. Nutr. 56, 72–81.PubMedCrossRefGoogle Scholar
  28. 28.
    Reaven, P., Parthasarathy, S., Grasse, B.J., Miller, E., Steinberg, D., and Witztum, J.L. (1993) Effects of oleate-rich and linoleate-rich diets on the susceptibility of low density lipoprotein to oxidative modification in mildly hypercholesterolemic subjects. J. Clin. Invest. 91, 668–676.PubMedCrossRefGoogle Scholar
  29. 29.
    Lada, A.T. and Rudel, L.L. (2003) Dietary monounsaturated versus polyunsaturated fatty acids: which is really better for protection from coronary heart disease? Curr. Opin. Lipidol. 14, 41–46.PubMedCrossRefGoogle Scholar
  30. 30.
    Giessauf, A., van Wickern, B., Simat, T., Steinhart, H., and Esterbauer, H. (1996) Formation of N-formylkynurenine suggests the involvement of apolipoprotein B-100 centered tryptophan radicals in the initiation of LDL lipid peroxidation. FEBS Lett. 389, 136–140.PubMedCrossRefGoogle Scholar
  31. 31.
    Miller, Y.I., Felikman, Y., and Shaklai, N. (1996) Hemoglobin induced apolipoprotein B crosslinking in low-density lipoprotein peroxidation. Arch. Biochem. Biophys. 326, 252–260.PubMedCrossRefGoogle Scholar
  32. 32.
    Alaiz, M., Beppu, M., Ohishi, K., and Kikugawa, K. (1994) Modification of delipidated apoprotein B of low density lipoprotein by lipid oxidation products in relation to macrophage scavenger receptor binding. Biol. Pharm. Bull. 17, 51–57.PubMedGoogle Scholar
  33. 33.
    Picard, S., Parthasarathy, S., Fruebis, J., and Witztum, J.L. (1992) Aminoguanidine inhibits oxidative modification of low density lipoprotein protein and the subsequent increase in uptake by macrophage scavenger receptors. Proc. Natl. Acad. Sci. USA 89, 6876–6880.PubMedCrossRefGoogle Scholar
  34. 34.
    Van Antwerpen, P., Legssyer, I., Zouaoui Boudjeltia, K., Babar, S., Moreau, P., Moguilevsky, N., Vanhaeverbeek, M., Ducobu, J., and Neve, J. (2006) Captopril inhibits the oxidative modification of apolipoprotein B-100 caused by myeloperoxidase in a comparative in vitro assay of angiotensin converting enzyme inhibitors. Eur. J. Pharmacol. 537, 31–36.PubMedCrossRefGoogle Scholar
  35. 35.
    Salonen, J.T., Yla-Herttuala, S., Yamamoto, R., Butler, S., Korpela, H., Salonen, R., Nyyssonen, K., Palinski, W., and Witztum, J.L. (1992) Autoantibody against oxidised LDL and progression of carotid atherosclerosis [see comments]. Lancet 339, 883–887.PubMedCrossRefGoogle Scholar
  36. 36.
    Palinski, W., Horkko, S., Miller, E., Steinbrecher, U.P., Powell, H.C., Curtiss, L.K., and Witztum, J.L. (1996) Cloning of monoclonal autoantibodies to epitopes of oxidized lipoproteins from apolipoprotein E-deficient mice. Demonstration of epitopes of oxidized low density lipoprotein in human plasma. J. Clin. Invest. 98, 800–814.PubMedCrossRefGoogle Scholar
  37. 37.
    Nakajima, T., Sakagishi, Y., Katahira, T., Nagata, A., Kuwae, T., Nakamura, H., Inoue, I., Takahashi, K., Katayama, S., and Komoda, T. (1995) Characterization of a specific monoclonal antibody 9F5-3a and the development of assay system for oxidized HDL. Biochem. Biophys. Res. Commun. 217, 407–411.PubMedCrossRefGoogle Scholar
  38. 38.
    Shao, B., O‘Brien, K.D., McDonald, T.O., Fu, X., Oram, J.F., Uchida, K., and Heinecke, J.W. (2005) Acrolein modifies apolipoprotein A-I in the human artery wall. Ann. NY Acad. Sci. 1043, 396–403.PubMedCrossRefGoogle Scholar
  39. 39.
    Cushing, S.D., Berliner, J.A., Valente, A.J., Territo, M.C., Navab, M., Parhami, F., Gerrity, R., Schwartz, C.J., and Fogelman, A.M. (1990) Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc. Natl. Acad. Sci. USA 87, 5134–5138.PubMedCrossRefGoogle Scholar
  40. 40.
    Liao, F., Berliner, J.A., Mehrabian, M., Navab, M., Demer, L.L., Lusis, A.J., and Fogelman, A.M. (1991) Minimally modified low density lipoprotein is biologically active in vivo in mice [published erratum appeared in J. Clin. Invest. 88, 721, 1991]. J. Clin. Invest. 87, 2253–2257.PubMedCrossRefGoogle Scholar
  41. 41.
    Parthasarathy, S., Fong, L.G., Otero, D., and Steinberg, D. (1987) Recognition of solubilized apoproteins from delipidated, oxidized low density lipoprotein (LDL) by the acetyl-LDL receptor. Proc. Natl. Acad. Sci. USA 84, 537–540.PubMedCrossRefGoogle Scholar
  42. 42.
    Sparrow, C.P., Parthasarathy, S., and Steinberg, D. (1989) A macrophage receptor that recognizes oxidized low density lipoprotein but not acetylated low density lipoprotein. J. Biol. Chem. 264, 2599–2604.PubMedGoogle Scholar
  43. 43.
    Morel, D.W., Hessler, J.R., and Chisolm, G.M. (1983) Low density lipoprotein cytotoxicity induced by free radical peroxidation of lipid. J. Lipid. Res. 24, 1070–1076.PubMedGoogle Scholar
  44. 44.
    Hoff, H.F., O‘Neil, J., Chisolm, G.M.D., Cole, T.B., Quehenberger, O., Esterbauer, H., and Jurgens, G. (1989) Modification of low density lipoprotein with 4-hydroxynonenal induces uptake by macrophages. Arteriosclerosis 9, 538–549.PubMedGoogle Scholar
  45. 45.
    Tertov, V.V., Kaplun, V.V., Dvoryantsev, S.N., and Orekhov, A.N. (1995) Apolipoprotein B-bound lipids as a marker for evaluation of low density lipoprotein oxidation in vivo. Biochem. Biophys. Res. Commun. 214, 608–613.PubMedCrossRefGoogle Scholar
  46. 46.
    Parthasarathy, S., and Barnett, J. (1990) Phospholipase A2 activity of low density lipoprotein: evidence for an intrinsic phospholipase A2 activity of apoprotein B-100. Proc. Natl. Acad. Sci. USA 87, 9741–9745.PubMedCrossRefGoogle Scholar
  47. 47.
    Sparrow, C.P., Parthasarathy, S., and Steinberg, D. (1988) Enzymatic modification of low density lipoprotein by purified lipoxygenase plus phospholipase A2 mimics cell-mediated oxidative modification. J. Lipid Res. 29, 745–753.PubMedGoogle Scholar
  48. 48.
    Parthasarathy, S., Wieland, E., and Steinberg, D. (1989) A role for endothelial cell lipoxygenase in the oxidative modification of low density lipoprotein. Proc. Natl. Acad. Sci. USA 86, 1046–1050.PubMedCrossRefGoogle Scholar
  49. 49.
    Cathcart, M.K., McNally, A.K., and Chisolm, G.M. (1991) Lipoxygenase-mediated transformation of human low density lipoprotein to an oxidized and cytotoxic complex. J. Lipid Res. 32, 63–70.PubMedGoogle Scholar
  50. 50.
    Rankin, S.M., Parthasarathy, S., and Steinberg, D. (1991) Evidence for a dominant role of lipoxygenase(s) in the oxidation of LDL by mouse peritoneal macrophages. J. Lipid Res. 32, 449–456.PubMedGoogle Scholar
  51. 51.
    Sigal, E., Laughton, C.W., and Mulkins, M.A. (1994) Oxidation, lipoxygenase, and atherogenesis. Ann. NY Acad. Sci. 714, 211–224.PubMedCrossRefGoogle Scholar
  52. 52.
    Kuhn, H., Belkner, J., Suzuki, H., and Yamamoto, S. (1994) Oxidative modification of human lipoproteins by lipoxygenases of different positional specificities. J. Lipid Res. 35, 1749–1759.PubMedGoogle Scholar
  53. 53.
    Kuhn, H., and Chan, L. (1997) The role of 15-lipoxygenase in atherogenesis: pro- and antiatherogenic actions. Curr. Opin. Lipidol. 8, 111–117.PubMedCrossRefGoogle Scholar
  54. 54.
    Heinecke, J.W., Rosen, H., and Chait, A. (1984) Iron and copper promote modification of low density lipoprotein by human arterial smooth muscle cells in culture. J. Clin. Invest. 74, 1890–1894.PubMedCrossRefGoogle Scholar
  55. 55.
    Quehenberger, O., Jurgens, G., Zadravec, S., and Esterbauer, H. (1988) Oxidation of human low density lipoprotein initiated by copper (II) chloride. Basic Life Sci. 49, 387–390.PubMedGoogle Scholar
  56. 56.
    Parthasarathy, S., Fong, L.G., Quinn, M.T., and Steinberg, D. (1990) Oxidative modification of LDL: comparison between cell-mediated and copper-mediated modification. Eur. Heart. J. 11 Suppl E, 83–87.PubMedGoogle Scholar
  57. 57.
    Ehrenwald, E., Chisolm, G.M., and Fox, P.L. (1994) Intact human ceruloplasmin oxidatively modifies low density lipoprotein. J. Clin. Invest. 93, 1493–1501.PubMedCrossRefGoogle Scholar
  58. 58.
    Lamb, D.J. and Leake, D.S. (1994) Acidic pH enables ceruloplasmin to catalyse the modification of low- density lipoprotein. FEBS Lett. 338, 122–126.PubMedCrossRefGoogle Scholar
  59. 59.
    Balla, G., Jacob, H.S., Eaton, J.W., Belcher, J.D., and Vercellotti, G.M. (1991) Hemin: a possible physiological mediator of low density lipoprotein oxidation and endothelial injury. Arterioscler. Thromb. Vasc. Biol. 11, 1700–1711.Google Scholar
  60. 60.
    Sakurai, T., Kimura, S., Nakano, M., and Kimura, H. (1991) Oxidative modification of glycated low density lipoprotein in the presence of iron. Biochem. Biophys. Res. Commun. 177, 433–439.PubMedCrossRefGoogle Scholar
  61. 61.
    Wieland, E., Parthasarathy, S., and Steinberg, D. (1993) Peroxidase-dependent metal-independent oxidation of low density lipoprotein in vitro: a model for in vivo oxidation? Proc. Natl. Acad. Sci. USA 90, 5929–5933.PubMedCrossRefGoogle Scholar
  62. 62.
    Savenkova, M.L., Mueller, D.M., and Heinecke, J.W. (1994) 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.PubMedGoogle Scholar
  63. 63.
    Natella, F., Nardini, M., Ursini, F., and Scaccini, C. (1998) Oxidative modification of human low-density lipoprotein by horseradish peroxidase in the absence of hydrogen peroxide. Free Radic. Res. 29, 427–434.PubMedCrossRefGoogle Scholar
  64. 64.
    Darley-Usmar, V.M., Hogg, N., O‘Leary, V.J., Wilson, M.T., and Moncada, S. (1992) The simultaneous generation of superoxide and nitric oxide can initiate lipid peroxidation in human low density lipoprotein. Free Radic. Res. Commun. 17, 9–20.PubMedCrossRefGoogle Scholar
  65. 65.
    Graham, A., Hogg, N., Kalyanaraman, B., O‘Leary, V., Darley-Usmar, V., and Moncada, S. (1993) Peroxynitrite modification of low-density lipoprotein leads to recognition by the macrophage scavenger receptor. FEBS Lett. 330, 181–185.PubMedCrossRefGoogle Scholar
  66. 66.
    Panasenko, O.M., Briviba, K., Klotz, L.O., and Sies, H. (1997) Oxidative modification and nitration of human low-density lipoproteins by the reaction of hypochlorous acid with nitrite. Arch. Biochem. Biophys. 343, 254–259.PubMedCrossRefGoogle Scholar
  67. 67.
    Parthasarathy, S. (1987) Oxidation of low-density lipoprotein by thiol compounds leads to its recognition by the acetyl LDL receptor. Biochim. Biophys. Acta. 917, 337–340.PubMedGoogle Scholar
  68. 68.
    Heinecke, J.W., Kawamura, M., Suzuki, L., and Chait, A. (1993) Oxidation of low density lipoprotein by thiols: superoxide-dependent and -independent mechanisms. J. Lipid Res. 34, 2051–2061.PubMedGoogle Scholar
  69. 69.
    Sparrow, C.P. and Olszewski, J. (1993) Cellular oxidation of low density lipoprotein is caused by thiol production in media containing transition metal ions. J. Lipid Res. 34, 1219–1228.PubMedGoogle Scholar
  70. 70.
    Wood, J.L. and Graham, A. (1995) The role of thiols in oxidation of low-density lipoprotein by macrophages. Biochem. Soc. Trans. 23, 242S.PubMedGoogle Scholar
  71. 71.
    Lynch, S.M. and Frei, B. (1993) Mechanisms of copper- and iron-dependent oxidative modification of human low density lipoprotein. J. Lipid Res. 34, 1745–1753.PubMedGoogle Scholar
  72. 72.
    Napoli, C., Ambrosio, G., Palumbo, G., Elia, P.P., and Chiariello, M. (1991) Human low-density lipoproteins are peroxidized by free radicals via chain reactions triggered by the superoxide radical. Cardiologia 36, 527–532.PubMedGoogle Scholar
  73. 73.
    Jessup, W., Simpson, J.A., and Dean, R.T. (1993) Does superoxide radical have a role in macrophage-mediated oxidative modification of LDL? Atherosclerosis 99, 107–120.PubMedCrossRefGoogle Scholar
  74. 74.
    Aviram, M., Rosenblat, M., Etzioni, A., and Levy, R. (1996) Activation of NADPH oxidase required for macrophage-mediated oxidation of low-density lipoprotein. Metabolism 45, 1069–1079.PubMedCrossRefGoogle Scholar
  75. 75.
    Montgomery, R.R., Nathan, C.F., and Cohn, Z.A. (1986) Effects of reagent and cell-generated hydrogen peroxide on the properties of low density lipoprotein. Proc. Natl. Acad. Sci. USA 83, 6631–6635.PubMedCrossRefGoogle Scholar
  76. 76.
    Hiramatsu, K., Rosen, H., Heinecke, J.W., Wolfbauer, G., and Chait, A. (1987) Superoxide initiates oxidation of low density lipoprotein by human monocytes. Arteriosclerosis. 7, 55–60.PubMedGoogle Scholar
  77. 77.
    Steinbrecher, U.P. (1988) Role of superoxide in endothelial-cell modification of low-density lipoproteins. Biochim. Biophys. Acta 959, 20–30.PubMedGoogle Scholar
  78. 78.
    Cathcart, M.K., McNally, A.K., Morel, D.W., and Chisolm, G.M.D. (1989) Superoxide anion participation in human monocyte-mediated oxidation of low-density lipoprotein and conversion of low-density lipoprotein to a cytotoxin. J. Immunol. 142, 1963–1969.PubMedGoogle Scholar
  79. 79.
    Kawabe, Y., Cynshi, O., Takashima, Y., Suzuki, T., Ohba, Y., and Kodama, T. (1994) Oxidation-induced aggregation of rabbit low-density lipoprotein by azo initiator. Arch. Biochem. Biophys. 310, 489–496.PubMedCrossRefGoogle Scholar
  80. 80.
    Noguchi, N., Gotoh, N., and Niki, E. (1994) Effects of ebselen and probucol on oxidative modifications of lipid and protein of low density lipoprotein induced by free radicals. Biochim. Biophys. Acta 1213, 176–182.PubMedGoogle Scholar
  81. 81.
    Leonhardt, W., Bergmann, R., and Hanefeld, M. (1997) Initiation of LDL oxidation by copper ions or AAPH yields different kinetic parameters which are correlated [letter]. Clin. Chim. Acta 259, 195–197.PubMedCrossRefGoogle Scholar
  82. 82.
    Kim, J.G., Sabbagh, F., Santanam, N., Wilcox, J.N., Medford, R.M., and Parthasarathy, S. (1997) Generation of a polyclonal antibody against lipid peroxide-modified proteins. Free Radic. Biol. Med. 23, 251–259.PubMedCrossRefGoogle Scholar
  83. 83.
    Dinis, T.C., Santosa, C.L., and Almeida, L.M. (2002) The apoprotein is the preferential target for peroxynitrite-induced LDL damage protection by dietary phenolic acids. Free Radic. Res. 36, 531–543.PubMedCrossRefGoogle Scholar
  84. 84.
    Heinecke, J.W. (1997) Pathways for oxidation of low density lipoprotein by myeloperoxidase: tyrosyl radical, reactive aldehydes, hypochlorous acid and molecular chlorine. Biofactors 6, 145–155.PubMedCrossRefGoogle Scholar
  85. 85.
    Cornicelli, J.A. and Trivedi, B.K. (1999) 15-Lipoxygenase and its inhibition: a novel therapeutic target for vascular disease. Curr. Pharm. Des. 5, 11–20.PubMedGoogle Scholar
  86. 86.
    Kuhn, H., Romisch, I., and Belkner, J. (2005) The role of lipoxygenase-isoforms in atherogenesis. Mol. Nutr. Food Res. 49, 1014–1029.PubMedCrossRefGoogle Scholar
  87. 87.
    Gugliucci Creriche, A. and Stahl, A.J. (1993) Glycation and oxidation of human low density lipoproteins reduces heparin binding and modifies charge. Scand. J. Clin. Lab Invest. 53, 125–132.PubMedCrossRefGoogle Scholar
  88. 88.
    Sanchez-Quesada, J.L., Perez, A., Caixas, A., Ordonmez-Llanos, J., Carreras, G., Payes, A., Gonzalez-Sastre, F., and de Leiva, A. (1996) Electronegative low density lipoprotein subform is increased in patients with short-duration IDDM and is closely related to glycaemic control. Diabetologia 39, 1469–1476.PubMedCrossRefGoogle Scholar
  89. 89.
    Demuth, K., Myara, I., Chappey, B., Vedie, B., Pech-Amsellem, M.A., Haberland, M.E., and Moatti, N. (1996) A cytotoxic electronegative LDL subfraction is present in human plasma. Arterioscler. Thromb. Vasc. Biol. 16, 773–783.PubMedGoogle Scholar
  90. 90.
    Dai, L., Zhang, Z., Winyard, P.G., Gaffney, K., Jones, H., Blake, D.R., and Morris, C.J. (1997) A modified form of low-density lipoprotein with increased electronegative charge is present in rheumatoid arthritis synovial fluid. Free Radic. Biol. Med. 22, 705–710.PubMedCrossRefGoogle Scholar
  91. 91.
    Moro, E., Zambon, C., Pianetti, S., Cazzolato, G., Pais, M., and Bittolo Bon, G. (1998) Electronegative low density lipoprotein subform (LDL-) is increased in type 2 (non-insulin-dependent) microalbuminuric diabetic patients and is closely associated with LDL susceptibility to oxidation. Acta Diabetol. 35, 161–164.PubMedCrossRefGoogle Scholar
  92. 92.
    Benitez, S., Perez, A., Sanchez-Quesada, J.L., Wagner, A.M., Rigla, M., Arcelus, R., Jorba, O., and Ordonez-Llanos, J. (2007) Electronegative low-density lipoprotein subfraction from type 2 diabetic subjects is proatherogenic and unrelated to glycemic control. Diabetes. Metab. Res. Rev. 23, 26–34.Google Scholar
  93. 93.
    Sanchez-Quesada, J.L., Camacho, M., Anton, R., Benitez, S., Vila, L., and Ordonez-Llanos, J. (2003) Electronegative LDL of FH subjects: chemical characterization and induction of chemokine release from human endothelial cells. Atherosclerosis 166, 261–270.PubMedCrossRefGoogle Scholar
  94. 94.
    Parasassi, T., Bittolo-Bon, G., Brunelli, R., Cazzolato, G., Krasnowska, E.K., Mei, G., Sevanian, A., and Ursini, F. (2001) Loss of apoB-100 secondary structure and conformation in hydroperoxide rich, electronegative LDL(-). Free Radic. Biol. Med. 31, 82–89.PubMedCrossRefGoogle Scholar
  95. 95.
    Barros, M.R., Bertolami, M.C., Abdalla, D.S., and Ferreira, W.P. (2006) Identification of mildly oxidized low-density lipoprotein (electronegative LDL) and its auto-antibodies IgG in children and adolescents hypercholesterolemic offsprings. Atherosclerosis 184, 103–107.PubMedCrossRefGoogle Scholar
  96. 96.
    Yamamoto, K. and Niki, E. (1988) Interaction of alpha-tocopherol with iron: antioxidant and prooxidant effects of alpha-tocopherol in the oxidation of lipids in aqueous dispersions in the presence of iron. Biochim. Biophys. Acta 958, 19–23.PubMedGoogle Scholar
  97. 97.
    Bowry, V.W., Ingold, K.U., and Stocker, R. (1992) Vitamin E in human low-density lipoprotein. When and how this antioxidant becomes a pro-oxidant. Biochem. J. 288, 341–344.PubMedGoogle Scholar
  98. 98.
    Santanam, N. and Parthasarathy, S. (1995) Paradoxical actions of antioxidants in the oxidation of low density lipoprotein by peroxidases. J. Clin. Invest. 95, 2594–2600.PubMedCrossRefGoogle Scholar
  99. 99.
    Santanam, N., and Parthasarathy, S. (1995) Cellular cysteine generation does not contribute to the initiation of LDL oxidation. J. Lipid Res. 36, 2203–2211.PubMedGoogle Scholar
  100. 100.
    Palinski, W., Rosenfeld, M.E., Yla-Herttuala, S., Gurtner, G.C., Socher, S.S., Butler, S.W., Parthasarathy, S., Carew, T.E., Steinberg, D., and Witztum, J.L. (1989) Low density lipoprotein undergoes oxidative modification in vivo. Proc. Natl. Acad. Sci. USA 86, 1372–1376.PubMedCrossRefGoogle Scholar
  101. 101.
    Aviram, M. (1990) Malondialdehyde affects the physico-chemical and biological characteristics of oxidized low density lipoprotein. Atherosclerosis 84, 141–143.PubMedCrossRefGoogle Scholar
  102. 102.
    Lecomte, E., Artur, Y., Chancerelle, Y., Herbeth, B., Galteau, M.M., Jeandel, C., and Siest, G. (1993) Malondialdehyde adducts to, and fragmentation of, apolipoprotein B from human plasma. Clin. Chim. Acta 218, 39–46.PubMedCrossRefGoogle Scholar
  103. 103.
    Requena, J.R., Fu, M.X., Ahmed, M.U., Jenkins, A.J., Lyons, T.J., Baynes, J.W., and Thorpe, S.R. (1997) Quantification of malondialdehyde and 4-hydroxynonenal adducts to lysine residues in native and oxidized human low-density lipoprotein. Biochem. J. 322, 317–325.PubMedGoogle Scholar
  104. 104.
    Lyons, T.J., Li, W., Wells-Knecht, M.C., and Jokl, R. (1994) Toxicity of mildly modified low-density lipoproteins to cultured retinal capillary endothelial cells and pericytes. Diabetes 43, 1090–1095.PubMedCrossRefGoogle Scholar
  105. 105.
    Scaccini, C., and Jialal, I. (1994) LDL modification by activated polymorphonuclear leukocytes: a cellular model of mild oxidative stress. Free Radic. Biol. Med. 16, 49–55.PubMedCrossRefGoogle Scholar
  106. 106.
    Sigari, F., Lee, C., Witztum, J.L., and Reaven, P.D. (1997) Fibroblasts that overexpress 15-lipoxygenase generate bioactive and minimally modified LDL. Arterioscler. Thromb. Vasc. Biol. 17, 3639–3645.PubMedGoogle Scholar
  107. 107.
    Kennedy, S., Fournet-Bourguignon, M.P., Breugnot, C., Castedo-Delrieu, M., Lesage, L., Reure, H., Briant, C., Leonce, S., Vilaine, J.P., and Vanhoutte, P.M. (2003) Cells derived from regenerated endothelium of the porcine coronary artery contain more oxidized forms of apolipoprotein-B-100 without a modification in the uptake of oxidized LDL. J. Vasc. Res. 40, 389–398.PubMedCrossRefGoogle Scholar
  108. 108.
    Esterbauer, H., Striegl, G., Puhl, H., and Rotheneder, M. (1989) Continuous monitoring of in vitro oxidation of human low density lipoprotein. Free Radic. Res. Commun. 6, 67–75.PubMedCrossRefGoogle Scholar
  109. 109.
    Moore, K.P., Darley-Usmar, V., Morrow, J., and Roberts, L.J., 2nd (1995) Formation of F2-isoprostanes during oxidation of human low-density lipoprotein and plasma by peroxynitrite. Circ. Res. 77, 335–341.PubMedGoogle Scholar
  110. 110.
    Moore, K., and Roberts, L.J., 2nd (1998) Measurement of lipid peroxidation. Free Radic. Res. 28, 659–671.PubMedCrossRefGoogle Scholar
  111. 111.
    Gaziano, J.M. (1994) Antioxidant vitamins and coronary artery disease risk. Am. J. Med. 97, 18S–21S; Discussion 22S–28S.PubMedCrossRefGoogle Scholar
  112. 112.
    Rapola, J.M., Virtamo, J., Ripatti, S., Huttunen, J.K., Albanes, D., Taylor, P.R., and Heinonen, O.P. (1997) Randomised trial of alpha-tocopherol and beta-carotene supplements on incidence of major coronary events in men with previous myocardial infraction [see comments]. Lancet 349, 1715–1720.PubMedCrossRefGoogle Scholar
  113. 113.
    Porkkala-Sarataho, E.K., Nyyssonen, M.K., Kaikkonen, J.E., Poulsen, H.E., Hayn, E.M., Salonen, R.M., and Salonen, J.T. (1998) A randomized, single-blind, placebo-controlled trial of the effects of 200 mg alpha-tocopherol on the oxidation resistance of atherogenic lipoproteins. Am. J. Clin. Nutr. 68, 1034–1041.PubMedGoogle Scholar
  114. 114.
    McKechnie, R., Rubenfire, M., and Mosca, L. (2002). Antioxidant nutrient supplementation and brachial reactivity in patients with coronary artery disease. J. Lab Clin. Med. 139, 133–139.PubMedCrossRefGoogle Scholar
  115. 115.
    Gey, K.F. (1993) Prospects for the prevention of free radical disease, regarding cancer and cardiovascular disease. Br. Med. Bull. 49, 679–699.PubMedGoogle Scholar
  116. 116.
    Blot, W.J., Li, J.Y., Taylor, P. Guo, W., Dawsey, S., Wang, G.Q., Yang, C.S., Zheng, S.F., Gail, M., Li, G.Y., et al. (1993) 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. 85, 1483–1492.PubMedCrossRefGoogle Scholar
  117. 117.
    Steinberg, D. (1995) Clinical trials of antioxidants in atherosclerosis: are we doing the right thing? Lancet 346, 36–38.PubMedCrossRefGoogle Scholar
  118. 118.
    Parthasarathy, S., Khan-Merchant, N., Penumetcha, M., Khan, B.V., and Santanam, N. (2001) Did the antioxidant trials fail to validate the oxidation hypothesis? Curr. Atheroscler. Rep. 3, 392–398.PubMedCrossRefGoogle Scholar
  119. 119.
    Heinecke, J.W. (2001) Is the emperor wearing clothes? Clinical trials of vitamin E and the LDL oxidation hypothesis. Arterioscler. Thromb. Vasc. Biol. 21, 1261–1264.PubMedCrossRefGoogle Scholar
  120. 120.
    Yusoff, K. (2002) Vitamin E in cardiovascular disease: has the die been cast? Asia Pac. J. Clin. Nutr. 7, S443–447.CrossRefGoogle Scholar
  121. 121.
    Heinecke, J.W. (2003) Clinical trials of vitamin E in coronary artery disease: is it time to reconsider the low-density lipoprotein oxidation hypothesis? Curr. Atheroscler. Rep. 5, 83–87.PubMedCrossRefGoogle Scholar
  122. 122.
    Ferns, G.A. and Lamb, D.J. (2004) What does the lipoprotein oxidation phenomenon mean? Biochem. Soc. Trans. 32, 160–163.PubMedCrossRefGoogle Scholar
  123. 123.
    Mowri, H., Chinen, K., Ohkuma, S., and Takano, T. (1986) Peroxidized lipids isolated by HPLC from atherosclerotic aorta. Biochem. Int. 12, 347–352.PubMedGoogle Scholar
  124. 124.
    Carpenter, K.L., Wilkins, G.M., Fussell, B., Ballantine, J.A., Taylor, S.E., Mitchinson, M.J., and Leake, D.S. (1994) Production of oxidized lipids during modification of low-density lipoprotein by macrophages or copper. Biochem. J. 304, 625–633.PubMedGoogle Scholar
  125. 125.
    Folcik, V.A., Nivar-Aristy, R.A., Krajewski, L.P., and Cathcart, M.K. (1995) Lipoxygenase contributes to the oxidation of lipids in human atherosclerotic plaques. J. Clin. Invest. 96, 504–510.PubMedCrossRefGoogle Scholar
  126. 126.
    Staprans, I., Rapp, J.H., Pan, X.M., Hardman, D.A., and Feingold, K.R. (1996) Oxidized lipids in the diet accelerate the development of fatty streaks in cholesterol-fed rabbits. Arterioscler. Thromb. Vasc. Biol. 16, 533–538.PubMedGoogle Scholar
  127. 127.
    Berliner, J., Leitinger, N., Watson, A., Huber, J., Fogelman, A., and Navab, M. (1997) Oxidized lipids in atherogenesis: formation, destruction and action. Thromb. Haemost. 78, 195–199.PubMedGoogle Scholar
  128. 128.
    Parthasarathy, S., Santanam, N., Ramachandran, S., and Meilhac, O. (2000) Potential role of oxidized lipids and lipoproteins in antioxidant defense [In Process Citation]. Free Radic. Res. 33, 197–215.PubMedCrossRefGoogle Scholar
  129. 129.
    Navab, M., Hama, S.Y., Reddy, S.T., Ng, C.J., Van Lenten, B.J., Laks, H., and Fogelman, A.M. (2002) Oxidized lipids as mediators of coronary heart disease. Curr. Opin. Lipidol. 13, 363–372.PubMedCrossRefGoogle Scholar
  130. 130.
    Birukov, K.G. (2006) Oxidized lipids: the two faces of vascular inflammation. Curr. Atheroscler. Rep. 8, 223–231.PubMedCrossRefGoogle Scholar
  131. 131.
    Salmon, S., Maziere, C., Theron, L., Beucler, I., Ayrault-Jarrier, M., Goldstein, S., and Polonovski, J. (1987) Immunological detection of low-density lipoproteins modified by malondialdehyde in vitro or in vivo. Biochim. Biophys. Acta. 920, 215–220.PubMedGoogle Scholar
  132. 132.
    Parums, D.V., Brown, D.L., and Mitchinson, M.J. (1990) Serum antibodies to oxidized low-density lipoprotein and ceroid in chronic periaortitis. Arch. Pathol. Lab. Med. 114, 383–387.PubMedGoogle Scholar
  133. 133.
    Virella, G., Virella, I., Leman, R.B., Pryor, M.B., and Lopes-Virella, M.F. (1993) Anti-oxidized low-density lipoprotein antibodies in patients with coronary heart disease and normal healthy volunteers. Int. J. Clin. Lab Res. 23, 95–101.PubMedCrossRefGoogle Scholar
  134. 134.
    Holvoet, P., Perez, G., Zhao, Z., Brouwers, E., Bernar, H., and Collen, D. (1995) Malondialdehyde-modified low density lipoproteins in patients with atherosclerotic disease. J. Clin. Invest. 95, 2611–2619.PubMedCrossRefGoogle Scholar
  135. 135.
    Festa, A., Kopp, H.P., Schernthaner, G., and Menzel, E.J. (1998) Autoantibodies to oxidised low density lipoproteins in IDDM are inversely related to metabolic control and microvascular complications. Diabetologia 41, 350–356.PubMedCrossRefGoogle Scholar
  136. 136.
    Lehtimaki, T., Lehtinen, S., Solakivi, T., Nikkila, M., Jaakkola, O., Jokela, H., Yla-Herttuala, S., Luoma, J.S., Koivula, T., and Nikkari, T. (1999) Autoantibodies against oxidized low density lipoprotein in patients with angiographically verified coronary artery disease [In Process Citation]. Arterioscler. Thromb. Vasc. Biol. 19, 23–27.PubMedGoogle Scholar
  137. 137.
    Frostegard, J., Wu, R. Lemne, C., Thulin, T., Witztum, J.L., and de Faire, U. (2003) Circulating oxidized low-density lipoprotein is increased in hypertension. Clin. Sci. (London) 105, 615–620.CrossRefGoogle Scholar
  138. 138.
    Herrick, A.L., Illingworth, K.J., Hollis, S., Gomez-Zumaquero, J.M., and Tinahones, F.J. (2001) Antibodies against oxidized low-density lipoproteins in systemic sclerosis. Rheumatology (Oxford) 40, 401–405.CrossRefGoogle Scholar
  139. 139.
    Tanaga, K., Bujo, H., Inoue, M., Mikami, K., Kotani, K., Takahashi, K., Kanno, T., and Saito, Y. (2002) Increased circulating malondialdehyde-modified LDL levels in patients with coronary artery diseases and their association with peak sizes of LDL particles. Arterioscler. Thromb. Vasc. Biol. 22, 662–666.PubMedCrossRefGoogle Scholar
  140. 140.
    Meraviglia, M.V., Maggi, E., Bellomo, G., Cursi, M., Fanelli, G., and Minicucci, F. (2002) Autoantibodies against oxidatively modified lipoproteins and progression of carotid restenosis after carotid endarterectomy. Stroke 33, 1139–1141.PubMedCrossRefGoogle Scholar
  141. 141.
    Hsu, R.M., Devaraj, S., and Jialal, I. (2002) Autoantibodies to oxidized low-density lipoprotein in patients with type 2 diabetes mellitus. Clin. Chim. Acta 317, 145–150.PubMedCrossRefGoogle Scholar
  142. 142.
    Tsimikas, S., Bergmark, C., Beyer, R.W., Patel, R., Pattison, J., Miller, E., Juliano, J., and Witztum, J.L. (2003) Temporal increases in plasma markers of oxidized low-density lipoprotein strongly reflect the presence of acute coronary syndromes. J. Am. Coll. Cardiol. 41, 360–370.PubMedCrossRefGoogle Scholar
  143. 143.
    Wang, J., Qiang, H., Zhang, C., Liu, X., Chen, D., and Wang, S. (2003) Detection of IgG-bound lipoprotein(a) immune complexes in patients with coronary heart disease. Clin. Chim. Acta 327, 115–122.PubMedCrossRefGoogle Scholar
  144. 144.
    Koskenmies, S., Vaarala, O., Widen, E., Kere, J., Palosuo, T., and Julkunen, H. (2004) The association of antibodies to cardiolipin, beta 2-glycoprotein I, prothrombin, and oxidized low-density lipoprotein with thrombosis in 292 patients with familial and sporadic systemic lupus erythematosus. Scand. J. Rheumatol. 33, 246–252.PubMedCrossRefGoogle Scholar
  145. 145.
    Luoma, J.S., Kareinen, A., Narvanen, O., Viitanen, L., Laakso, M., and Yla-Herttuala, S. (2005) Autoantibodies against oxidized LDL are associated with severe chest pain attacks in patients with coronary heart disease. Free Radic. Biol. Med. 39, 1660–1665.PubMedCrossRefGoogle Scholar
  146. 146.
    Maggi, E., Finardi, G., Poli, M., Bollati, P., Filipponi, M., Stefano, P.L., Paolini, G., Grossi, A., Clot, P., Albano, E., et al. (1993) Specificity of autoantibodies against oxidized LDL as an additional marker for atherosclerotic risk. Coron. Artery Dis. 4, 1119–1122.PubMedCrossRefGoogle Scholar
  147. 147.
    Bui, M.N., Sack, M.N., Moutsatsos, G., Lu, D.Y., Katz, P., McCown, R., Breall, J.A., and Rackley, C.E. (1996) Autoantibody titers to oxidized low-density lipoprotein in patients with coronary atherosclerosis. Am. Heart J. 131, 663–667.PubMedCrossRefGoogle Scholar
  148. 148.
    Uusitupa, M.I., Niskanen, L., Luoma, J., Vilja, P., Mercuri, M., Rauramaa, R., and Yla-Herttuala, S. (1996) Autoantibodies against oxidized LDL do not predict atherosclerotic vascular disease in non-insulin-dependent diabetes mellitus. Arterioscler. Thromb. Vasc. Biol. 16, 1236–1242.PubMedGoogle Scholar
  149. 149.
    van de Vijver, L.P., Steyger, R., van Poppel, G., Boer, J.M., Kruijssen, D.A., Seidell, J.C., and Princen, H.M. (1996) Autoantibodies against MDA-LDL in subjects with severe and minor atherosclerosis and healthy population controls. Atherosclerosis 122, 245–253.PubMedCrossRefGoogle Scholar
  150. 150.
    Kim, J.G., Taylor, W.R., and Parthasarathy, S. (1999) Demonstration of the presence of lipid peroxide-modified proteins in human atherosclerotic lesions using a novel lipid peroxide-modified anti-peptide antibody. Atherosclerosis 143, 335–340.PubMedCrossRefGoogle Scholar
  151. 151.
    Tsai, W.C., Li, Y.H., Chao, T.H., and Chen, J.H. (2002) Relation between antibody against oxidized low-density lipoprotein and extent of coronary atherosclerosis. J. Formos. Med. Assoc. 101, 681–684.PubMedGoogle Scholar
  152. 152.
    Radulescu, L., Stancu, C., and Antohe, F. (2004) Antibodies against human oxidized low-density lipoprotein (LDL) as markers for human plasma modified lipoproteins. Med. Sci. Monit. 10, BR207–214.PubMedGoogle Scholar
  153. 153.
    Tsimikas, S. (2006) Oxidized low-density lipoprotein biomarkers in atherosclerosis. Curr. Atheroscler. Rep. 8, 55–61.PubMedCrossRefGoogle Scholar
  154. 154.
    Moguilevsky, N., Zouaoui Boudjeltia, K., Babar, S., Delree, P., Legssyer, I., Carpentier, Y., Vanhaeverbeek, M., and Ducobu, J. (2004) Monoclonal antibodies against LDL progressively oxidized by myeloperoxidase react with ApoB-100 protein moiety and human atherosclerotic lesions. Biochem. Biophys. Res. Commun. 323, 1223–1228.PubMedCrossRefGoogle Scholar
  155. 155.
    Nambi, V. (2005) The use of myeloperoxidase as a risk marker for atherosclerosis. Curr. Atheroscler. Rep. 7, 127–131.PubMedCrossRefGoogle Scholar
  156. 156.
    Yamaguchi, Y., Yoshikawa, N., Kagota, S., Nakamura, K., Haginaka, J., and Kunitomo, M. (2006) Elevated circulating levels of markers of oxidative-nitrative stress and inflammation in a genetic rat model of metabolic syndrome. Nitric Oxide 15, 380–386.PubMedCrossRefGoogle Scholar
  157. 157.
    Parthasarathy, S. et al. (1999) J. Lipid Res. 40 , 2143–2157.PubMedGoogle Scholar

Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Sampath Parthasarathy
    • 1
  • Achuthan Raghavamenon
    • 2
  • Mahdi Omar Garelnabi
    • 1
  • Nalini Santanam
    • 3
  1. 1.Division of Cardiothoracic SurgeryThe Ohio State University Medical CenterColumbusUSA
  2. 2.Department of Environmental Toxicology and the Health Research CenterSouthern University and A&M CollegeBaton RougeUSA
  3. 3.Department of PharmacologyMarshall UniversityHuntingtonUSA

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