ABB  Vol.4 No.11 A , November 2013
Atherogenesis, the oxidative LDL modification hypothesis revisited
ABSTRACT

The commonly-accepted “oxidized LDL hypothesis of atherogenesis” is based on a large number of indirect evidence that shows that oxidatively-modified LDL plays a role in atherogenesis. Yet, the exact role is not clear. Some researchers think that oxidatively modified biomolecules initiate atherogenesis; others believe that they “only” promote this multifactorial process. Regardless of the exact mechanism responsible for the effect of peroxidation on atherogenesis, the “oxidative theory of AS” is apparently inconsistent with the results of meta-analysis, in which (the “expected”) significant correlation between CVD and oxidative stress (OS) was found only when the OS was evaluated on the basis of the plasma concentrations of malondialdehyde (MDA), often based on the concentration of thiobarbituric acid reactive substances (TBARS). Notably, even this association is questionable due to 1) poor reliability of the laboratory assay of MDA and 2) possible publication bias. Hence, it appears that the commonly accepted paradigm regarding the role of oxidative damage in the pathogenesis of CVD has been overestimated. Furthermore, the hypothesis is apparently inconsistent with the disappointing results of most of the clinical trials that were designed to reduce OS by means of supplementation of antioxidants, mostly vitamin E. These apparent inconsistencies do not contradict the oxidative modification hypothesis of AS. The source of the apparent contradictions is probably the oversimplified considerations on which the predictions have been based. Many reasonable arguments can be raised to explain the apparent contradictions, which means that our current knowledge is insufficient to test the relationship of oxidative stress to cardiovascular disease.


Cite this paper
Lichtenberg, D. and Pinchuk, I. (2013) Atherogenesis, the oxidative LDL modification hypothesis revisited. Advances in Bioscience and Biotechnology, 4, 48-61. doi: 10.4236/abb.2013.411A2007.
References
[1]   Terman, A. and Brunk, U.T. (2006) Oxidative stress, accumulation of biological “garbage”, and aging. Antioxidants & Redox Signaling, 8, 197-204.
http://dx.doi.org/10.1089/ars.2006.8.197

[2]   Droge, W. (2002) Free radicals in the physiological control of cell function. Physiological Reviews, 82, 47-95.

[3]   Finkel, T. (1998) Oxygen radicals and signaling. Current Opinion in Cell Biology, 10, 248-253.
http://dx.doi.org/10.1016/S0955-0674(98)80147-6

[4]   Halliwell, B. (2009) The wanderings of a free radical. Free Radical Biology and Medicine, 46, 531-542.
http://dx.doi.org/10.1016/j.freeradbiomed.2008.11.008

[5]   Halliwell, B., Gutteridge, J.M.C. and Cross, C.E. (1992) Free-radicals, antioxidants, and human-disease—Where are we now. Journal of Laboratory and Clinical Medicine, 119, 598-620.

[6]   Rattan, S.I.S. and Demirovic, D. (2010) Hormesis can and does work in humans. Dose-Response, 8, 58-63.
http://dx.doi.org/10.2203/dose-response.09-041.Rattan

[7]   Ristow, M., Zarse, K., Oberbach, A., Kloting, N., Birringer, M., Kiehntopf, M., et al. (2009) Antioxidants prevent health-promoting effects of physical exercise in humans. Proceedings of the National Academy of Sciences of the United States of America, 106, 8665-8670.
http://dx.doi.org/10.1073/pnas.0903485106

[8]   Valko, M., Leibfritz, D., Moncol, J., Cronin, M.T.D., Mazur, M. and Telser, J. (2007) Free radicals and antioxidants in normal physiological functions and human disease. International Journal of Biochemistry & Cell Biology, 39, 44-84.
http://dx.doi.org/10.1016/j.biocel.2006.07.001

[9]   Halliwell, B. and Gutteridge, G.M.C. (2007) Free radicals in biology and medicine. Oxford University Press, Oxford.

[10]   Martin, K.R. and Barrett, J.C. (2002) Reactive oxygen species as double-edged swords in cellular processes: Lowdose cell signaling versus high-dose toxicity. Human & Experimental Toxicology, 21, 71-75.
http://dx.doi.org/10.1191/0960327102ht213oa

[11]   Yedgar, S., Krimsky, M., Cohen, Y. and Flower, R.J. (2007) Treatment of inflammatory diseases by selective eicosanoid inhibition: A double-edged sword? Trends in Pharmacological Sciences, 28, 459-464.
http://dx.doi.org/10.1016/j.tips.2007.07.005

[12]   Harman, D. (1956) Aging: A theory based on free radical and radiation chemistry. Journal of Gerontology, 11, 298-300. http://dx.doi.org/10.1093/geronj/11.3.298

[13]   Jang, Y.C. and Van Remmen, H. (2009) The mitochondrial theory of aging: Insight from transgenic and knockout mouse models. Experimental Gerontology, 44, 256-260. http://dx.doi.org/10.1016/j.exger.2008.12.006

[14]   Lyketsos, C.G., Steinberg, M., Tschanz, J.T., Norton, M.C., Steffens, D.C. and Breitner, J.C.S. (2000) Mental and behavioral disturbances in dementia: Findings from the Cache County Study on Memory in Aging. American Journal of Psychiatry, 157, 708-714.
http://dx.doi.org/10.1176/appi.ajp.157.5.708

[15]   Perez, V.I., Bokov, A., Van Remmen, H., Mele, J., Ran, Q.T., Ikeno, Y., et al. (2009) Is the oxidative stress theory of aging dead? Biochimica et Biophysica Acta—General Subjects, 1790, 1005-1014.
http://dx.doi.org/10.1016/j.bbagen.2009.06.003

[16]   Ristow, M. and Schmeisser, S. (2011) Extending life span by increasing oxidative stress. Free Radical Biology and Medicine, 51, 327-336.
http://dx.doi.org/10.1016/j.freeradbiomed.2011.05.010

[17]   Cheeseman, K.H. and Slater, T.F. (1993) An introduction to free-radical biochemistry. British Medical Bulletin, 49, 481-493.

[18]   Gutteridge, J.M.C. (1993) Free-radicals in disease processes—A compilation of cause and consequence. Free Radical Research Communications, 19, 141-158.
http://dx.doi.org/10.3109/10715769309111598

[19]   Sies, H. (1991) Oxidative stress—From basic research to clinical-application. American Journal of Medicine, 91, S31-S38.
http://dx.doi.org/10.1016/0002-9343(91)90281-2

[20]   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. New England Journal of Medicine, 320, 915-924.

[21]   Brown, M.S. and Goldstein, J.L. (1986) A receptor-mediated pathway for cholesterol homeostasis. Science, 232, 34-47. http://dx.doi.org/10.1126/science.3513311

[22]   Goldstein, J.L., Ho, Y.K., Basu, S.K. and Brown, M.S. (1979) Binding-site on macrophages that mediates uptake and degradation of acetylated low-density lipoprotein, producing massive cholesterol deposition. Proceedings of the National Academy of Sciences of the United States of America, 76, 333-337.
http://dx.doi.org/10.1073/pnas.76.1.333

[23]   Chisolm, G.M. and Steinberg, D. (2000) The oxidative modification hypothesis of atherogenesis: An overview. Free Radical Biology and Medicine, 28, 1815-1826.
http://dx.doi.org/10.1016/S0891-5849(00)00344-0

[24]   Quinn, M.T., Parthasarathy, S. and Steinberg, D. (1985) Endothelial cell-derived chemotactic activity for mouse peritoneal-macrophages and the effects of modified forms of low-density lipoprotein. Proceedings of the National Academy of Sciences of the United States of America, 82, 5949-5953. http://dx.doi.org/10.1073/pnas.82.17.5949

[25]   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. Proceedings of the National Academy of Sciences of the United States of America, 84, 2995-2998.
http://dx.doi.org/10.1073/pnas.84.9.2995

[26]   Steinberg, D., Berliner, J.A., Burton, G.W., Carew, T.E., Chait, A., Chisolm, G.M. et al. (1992) Antioxidants in the prevention of human atherosclerosis. Summary of the Proceedings of a National Heart Lung and Blood Institute Workshop, 5-6 September 1991, Bethesda, Circulation, 85, 2338-2344.
http://dx.doi.org/10.1161/01.CIR.85.6.2337

[27]   Carew, T.E., Schwenke, D.C. and Steinberg, D. (1987) Antiatherogenic effect of probucol unrelated to its hypocholesterolemic effect—Evidence that antioxidants in vivo can selectively inhibit low-density-lipoprotein degradation in macrophage-rich fatty streaks and slow the progression of atherosclerosis in the Watanabe heritable hyperlipidemic rabbit. Proceedings of the National Academy of Sciences of the United States of America, 84, 7725-7729. http://dx.doi.org/10.1073/pnas.84.21.7725

[28]   Verlangieri, A.J. and Bush, M.J. (1992) Effects of Dalpha-tocopherol supplementation on experimentally induced primate atherosclerosis. Journal of the American College of Nutrition, 11, 131-138.

[29]   Witztum, J.L. and Steinberg, D. (2001) The oxidative modification hypothesis of atherosclerosis: Does it hold for humans? Trends in Cardiovascular Medicine, 11, 93-102. http://dx.doi.org/10.1016/S1050-1738(01)00111-6

[30]   Esterbauer, H., Rotheneder, M., Striegl, G., Waeg, G., Ashy, A., Sattler, W., et al. (1989) Vitamin-e and other lipophilic antioxidants protect Ldl against oxidation. Fett Wissenschaft Technologie-Fat Science Technology, 91, 316-324.

[31]   Pryor, W.A. (2000) Vitamin E and heart disease: Basic science to clinical intervention trials. Free Radical Biology and Medicine, 28, 141-164.
http://dx.doi.org/10.1016/S0891-5849(99)00224-5

[32]   Stocker, R. and Keaney, J.F. (2004) Role of oxidative modifications in atherosclerosis. Physiological Reviews, 84, 1381-1478. http://dx.doi.org/10.1152/physrev.00047.2003

[33]   Bjelakovic, G., Nikolova, D., Simonetti, R.G. and Gluud, C. (2004) Antioxidant supplements for prevention of gastrointestinal cancers: A systematic review and meta-analysis. Lancet, 364, 1219-1228.
http://dx.doi.org/10.1016/S0140-6736(04)17138-9

[34]   Miller, E.R., Pastor-Barriuso, R., Dalal, D., Riemersma, R.A., Appel, L.J. and Guallar, E. (2005) Meta-analysis: High-dosage vitamin E supplementation may increase allcause mortality. Annals of Internal Medicine, 142, 37-46.
http://dx.doi.org/10.7326/0003-4819-142-1-200501040-00110

[35]   Greenberg, E.R. (2005) Vitamin E supplements: Good in theory, but is the theory good? Annals of Internal Medicine, 142, 75-76.
http://dx.doi.org/10.7326/0003-4819-142-1-200501040-00112

[36]   Henriksen, T., Mahoney, E.M. and Steinberg, D. (1981) Enhanced macrophage degradation of low-density lipoprotein previously incubated with cultured endothelial cells: Recognition by receptors for acetylated low-density lipoproteins. Proceedings of the National Academy of Sciences of the United States of America, 78, 6499-6503.
http://dx.doi.org/10.1073/pnas.78.10.6499

[37]   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. Proceedings of the National Academy of Sciences of the United States of America, 81, 3883-3887.
http://dx.doi.org/10.1073/pnas.81.12.3883

[38]   Kita, T., Nagano, Y., Yokode, M., Ishii, K., Kume, N., Ooshima, A., Yoshida, H. and Kawai, C. (1987) Probucol prevents the progression of atherosclerosis in watanabe heritable hyperlipidemic rabbit, an animal-model for familial hypercholesterolemia. Proceedings of the National Academy of Sciences of the United States of America, 84, 5928-5931. http://dx.doi.org/10.1073/pnas.84.16.5928

[39]   Vaya, J. (2013) The association between biomarkers in the blood and carotid plaque composition-focusing on oxidized lipids, oxysterols and plaque status. Biochemical Pharmacology, 86, 15-18.
http://dx.doi.org/10.1016/j.bcp.2013.01.025

[40]   Levitan, I., Volkov, S. and Subbaiah, P.V. (2010) Oxidized LDL: Diversity, patterns of recognition, and pathophysiology. Antioxidants & Redox Signaling, 13, 39-75.
http://dx.doi.org/10.1089/ars.2009.2733

[41]   Frank, J.S. and Fogelman, A.M. (1989) Ultrastructure of the intima in WHHL and cholesterol-fed rabbit aortas prepared by ultra-rapid freezing and freeze-etching. Journal of Lipid Research, 30, 967-978.

[42]   Khoo, J.C., Miller E., Mcloughlin P. and Steinberg D. (1988) Enhanced macrophage uptake of low-density lipoprotein after self-aggregation. Arteriosclerosis, 8, 348-358. http://dx.doi.org/10.1161/01.ATV.8.4.348

[43]   Lichtman, A.H., Binder C.J., Tsimikas S. and Witztum J.L. (2013) Adaptive immunity in atherogenesis: New insights and therapeutic approaches. Journal of Clinical Investigation, 123, 27-36.
http://dx.doi.org/10.1172/JCI63108

[44]   Halliwell, B. (2011) Free radicals and antioxidants—Quo vadis? Trends in Pharmacological Sciences, 32, 125-130.
http://dx.doi.org/10.1016/j.tips.2010.12.002

[45]   Curtiss, L.K. (2009) Reversing atherosclerosis? New England Journal of Medicine, 360, 1144-1146.
http://dx.doi.org/10.1056/NEJMcibr0810383

[46]   Lakota, K., Artenjak, A., Cucnik, S., Brguljan-Hitij, J., Cegovnik, B., Salobir, B. et al. (2012) Atherogenesis, inflammation and autoimmunity—An overview. In: Parthasarathy, S., Ed., Atherogenesis, InTech, 187-202.
http://dx.doi.org/10.5772/26811

[47]   Taleb, A., Witztum, J.L. and Tsimikas, S. (2011) Oxidized phospholipids on apoB-100-containing lipoproteins: A biomarker predicting cardiovascular disease and cardiovascular events. Biomarkers in Medicine, 5, 673-694.
http://dx.doi.org/10.2217/bmm.11.60

[48]   Dotan, Y., Lichtenberg, D. and Pinchuk, I. (2004) Lipid peroxidation cannot be used as a universal criterion of oxidative stress. Progress in Lipid Research, 43, 200-227.
http://dx.doi.org/10.1016/j.plipres.2003.10.001

[49]   Dotan, Y., Lichtenberg, D. and Pinchuk, I. (2012) Are CVD patients under oxidative stress? In: Parthasarathy, S., Ed., Atherogenesis, InTech, pp. 413-424.
http://dx.doi.org/10.5772/28181

[50]   Verhoye, E. and Langlois, M.R. (2009) Circulating oxidized low-density lipoprotein: A biomarker of atherosclerosis and cardiovascular risk? Clinical Chemistry and Laboratory Medicine, 47, 128-137.
http://dx.doi.org/10.1515/CCLM.2009.037

[51]   Jain, S.K., Mcvie, R., Meachum, Z.D. and Smith, T. (2000) Effect of LDL plus VLDL oxidizability and hyperglycemia on blood cholesterol, phospholipid and triglyceride levels in Type-I diabetic patients. Atherosclerosis, 149, 69-73.
http://dx.doi.org/10.1016/S0021-9150(99)00308-1

[52]   Hayden, K.M., Welsh-Bohmer, K.A., Wengreen, H.J., Zandi, P.P., Lyketsos, C.G. and Breitner, J.C.S. (2007) Risk of mortality with vitamin E supplements: The cache county study. American Journal of Medicine, 120, 180-184. http://dx.doi.org/10.1016/j.amjmed.2006.03.039

[53]   Jialal, I. and Devaraj, S. (2005) High-dosage vitamin E supplementation and all-cause mortality. Annals of Internal Medicine, 143, 155.
http://dx.doi.org/10.7326/0003-4819-143-2-200507190-00026

[54]   Blumberg, J.B. and Frei, B. (2007) Why clinical trials of vitamin E and cardiovascular diseases may be fatally flawed. Commentary on “The relationship between dose of vitamin E and suppression of oxidative stress in humans”. Free Radical Biology and Medicine, 43, 1374-1376.
http://dx.doi.org/10.1016/j.freeradbiomed.2007.08.017

[55]   Bjelakovic, G., Nikolova, D., Gluud, L.L., Simonetti, R.G. and Gluud, C. (2007) Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: Systematic review and meta-analysis. JAMA—Journal of the American Medical Association, 297, 842-857.
http://dx.doi.org/10.1001/jama.297.8.842

[56]   Miller, E.R., Appel, L.J., Guallar, E. and Pastor-Barriuso, R. (2005) High-dosage vitamin E supplementation and allcause mortality—Response. Annals of Internal Medicine, 143, 156-158.
http://dx.doi.org/10.7326/0003-4819-143-2-200507190-00029

[57]   Dotan, Y., Lichtenberg, D. and Pinchuk, I. (2009) No evidence supports vitamin E indiscriminate supplementation. Biofactors, 35, 469-473. http://dx.doi.org/10.1002/biof.61

[58]   Dotan, Y., Pinchuk, I., Lichtenberg, D. and Leshno, M. (2009) Decision analysis supports the paradigm that indiscriminate supplementation of vitamin E does more harm than good. Arteriosclerosis Thrombosis and Vascular Biology, 29, 1304-1309.
http://dx.doi.org/10.1161/ATVBAHA.108.178699

[59]   Muennig, P.A. and Gold, M.R. (2001) Using the years-of-healthy-life measure to calculate QALYs. American Journal of Preventive Medicine, 20, 35-39.
http://dx.doi.org/10.1016/S0749-3797(00)00261-0

[60]   Wade, L., Nadeem, N., Young, I.S., Woodside, J.V., Mc-Ginty, A., McMaster, C. and McEneny, J. (2013) α-tocopherol induces proatherogenic changes to HDL2 & HDL3: An in vitro and ex vivo investigation. Atherosclerosis, 226, 392-397.
http://dx.doi.org/10.1016/j.atherosclerosis.2012.11.032

[61]   Shao, B. and Heinecke, J.W. (2009) HDL, lipid peroxidetion, and atherosclerosis. Journal of Lipid Research, 50, 599-601. http://dx.doi.org/10.1194/jlr.E900001-JLR200

[62]   Navab, M., Reddy, S.T., Van Lenten, B.J. and Fogelman A.M. (2011) HDL and cardiovascular disease: Atherogenic and atheroprotective mechanisms. Nature Reviews Cardiology, 8, 222-232.
http://dx.doi.org/10.1038/nrcardio.2010.222

[63]   Toker, A., Kadi, M., Yildirim, A.K., Aksoy, H. and Akcay, F. (2009) Serum lipid profile paraoxonase and arylesterase activities in psoriasis. Cell Biochemistry and Function, 27, 176-180. http://dx.doi.org/10.1002/cbf.1553

[64]   Moradi, H., Pahl, M.V., Elahimehr, R. and Vaziri, N.D. (2009) Impaired antioxidant activity of high-density lipoprotein in chronic kidney disease. Translational Research, 153, 77-85. http://dx.doi.org/10.1016/j.trsl.2008.11.007

[65]   Raveh, O., Pinchuk, I., Schnitzer, E., Fainaru, M., Schaffer, Z. and Lichtenberg, D. (2000) Kinetic analysis of copper-induced peroxidation of HDL, autoaccelerated and tocopherol-mediated peroxidation. Free Radical Biology and Medicine, 29, 131-146.
http://dx.doi.org/10.1016/S0891-5849(00)00332-4

[66]   Brizzi, P., Tonolo, G., Carusillo, F., Malaguarnera, M., Maioli, M. and Musumeci, S. (2003) Plasma lipid composition and LDL oxidation. Clinical Chemistry and Laboratory Medicine, 41, 56-60.
http://dx.doi.org/10.1515/CCLM.2003.010

[67]   Chait, A., Brazg, R.L., Tribble, D.L. and Krauss, R.M. (1993) Susceptibility of small, dense, low-density lipoproteins to oxidative modification in subjects with the atherogenic lipoprotein phenotype, pattern-B. American Journal of Medicine, 94, 350-356.
http://dx.doi.org/10.1016/0002-9343(93)90144-E

[68]   Raveh, O., Pinchuk, I., Fainaru, M. and Lichtenberg, D. (2001) Kinetics of lipid peroxidation in mixtures of HDL and LDL, mutual effects. Free Radical Biology and Medicine, 31, 1486-1497.
http://dx.doi.org/10.1016/S0891-5849(01)00730-4

[69]   Ishigaki, Y., Katagiri, H., Gao, J., Yamada, T., Imai, J., Uno, K., et al. (2008) Impact of plasma oxidized low-density lipoprotein removal on atherosclerosis. Circulation, 118, 75-83.
http://dx.doi.org/10.1161/CIRCULATIONAHA.107.745174

[70]   Schnitzer, E., Fainaru, M. and Lichtenberg, D. (1995) Oxidation of low-density-lipoprotein upon sequential exposure to copper ions. Free Radical Research, 23, 137-149. http://dx.doi.org/10.3109/10715769509064028

[71]   Stafforini, D.M., Zimmerman, G.A., Mcintyre, T.M. and Prescott, S.M. (1992) The Paf acetylhydrolase from human plasma prevents oxidative modification of low-density-lipoprotein. Clinical Research, 40, A253.

[72]   Schnitzer, E., Pinchuk, I., Fainaru, M., Lichtenberg, D. and Yedgar, S. (1998) LDL-associated phospholipase A does not protect LDL against lipid peroxidation in vitro. Free Radical Biology and Medicine, 24, 1294-1303.
http://dx.doi.org/10.1016/S0891-5849(97)00454-1

[73]   Teiber, J.F., Draganov, D.I. and La Du, B.N. (2004) Purified human serum PON1 does not protect LDL against oxidation in the in vitro assays initiated with copper or AAPH. Journal of Lipid Research, 45, 2260-2268.
http://dx.doi.org/10.1194/jlr.M400213-JLR200

[74]   Fyrnys, B., Blencowe, C. and Deigner, H.P. (1995) Susceptibility of phospholipids of oxidizing LDL to enzymatic-hydrolysis modulates uptake by P388D1 macrophage-like cells. FEBS Letters, 357, 7-12.
http://dx.doi.org/10.1016/0014-5793(94)01312-O

[75]   Mackness, M.I., Arrol, S. and Durrington, P.N. (1991) Paraoxonase prevents accumulation of lipoperoxides in low-density-lipoprotein. FEBS Letters, 286, 152-154.
http://dx.doi.org/10.1016/0014-5793(91)80962-3

[76]   Mackness, M.I., Abbott, C., Arrol, S. and Durrington, P.N. (1993) The Role of high-density-lipoprotein and lipid-soluble antioxidant vitamins in inhibiting low-density lipoprotein oxidation. Biochemical Journal, 294, 829-834.

[77]   Aviram, M., Hardak, E., Vaya, J., Mahmood, S., Milo, S., Hoffman, A., et al. (2000) Human serum paraoxonases (PON1) Q and R selectively decrease lipid peroxides in human coronary and carotid atherosclerotic lesions PON1 esterase and peroxidase-like activities. Circulation, 101, 2510-2517. http://dx.doi.org/10.1161/01.CIR.101.21.2510

[78]   Mackness, M.I., Mackness, B., Durrington, P.N., Fogelman, A.M., Berliner, J., Lusis, A.J., et al. (1998) Paraoxonase and coronary heart disease. Current Opinion in Lipidology, 9, 319-324.
http://dx.doi.org/10.1097/00041433-199808000-00006

[79]   Mackness M.I., Durrington P.N. and Mackness B. (2000) How high-density lipoprotein protects against the effects of lipid peroxidation. Current Opinion in Lipidology, 11, 383-388. http://dx.doi.org/10.1097/00041433-200008000-00007

[80]   Rosenblat, M. and Aviram, M. (2009) Paraoxonases role in the prevention of cardiovascular diseases. Biofactors, 35, 98-104. http://dx.doi.org/10.1002/biof.16

[81]   Ng, C.J., Wadleigh, D.J., Gangopadhyay, A., Hama, S., Grijalva, V.R., Navab, M., Fogelman, A.M. and Reddy, S.T. (2001) Paraoxonase-2 is a ubiquitously expressed protein with antioxidant properties and is capable of preventing cell-mediated oxidative modification of low density lipoprotein. Journal of Biological Chemistry, 276, 44444-44449. http://dx.doi.org/10.1074/jbc.M105660200

[82]   Bowry, V.W., Stanley, K.K. and Stocker, R. (1992) Highdensity-lipoprotein is the major carrier of lipid hydroperoxides in human blood-plasma from fasting donors. Proceedings of the National Academy of Sciences of the United States of America, 89, 10316-10320.
http://dx.doi.org/10.1073/pnas.89.21.10316

[83]   Buettner, G.R. (1993) The pecking order of free-radicals and antioxidants: Lipid-peroxidation, α-tocopherol, and ascorbate. Archives of Biochemistry and Biophysics, 300, 535-543. http://dx.doi.org/10.1006/abbi.1993.1074

[84]   Shimonov, M., Pinchuk, I., Bor, A., Beigel, I., Fainaru, M., Rubin, M., et al. (1999) Susceptibility of serum lipids to copper-induced peroxidation correlates with the level of high density lipoprotein cholesterol. Lipids, 34, 255-259.
http://dx.doi.org/10.1007/s11745-999-0361-0

[85]   Tynkkynen, T., Mursu, J., Nurmi, T., Tuppurainen, K., Laatikainen, R. and Soininen, P. (2012) NMR protocol for determination of oxidation susceptibility of serum lipids and application of the protocol to a chocolate study. Metabolomics, 8, 386-398.
http://dx.doi.org/10.1007/s11306-011-0323-2

[86]   Williams, K.J. and Fisher, E.A. (2005) Oxidation, lipoproteins, and atherosclerosis: Which is wrong, the antioxidants or the theory? Current Opinion in Clinical Nutrition and Metabolic Care, 8, 139-146.
http://dx.doi.org/10.1097/00075197-200503000-00006

[87]   Wu, B.J., Kathir, K., Witting, P.K., Beck, K., Choy, K., Li, C., et al. (2006) Antioxidants protect from atherosclerosis by a heme oxygenase-1 pathway that is independent of free radical scavenging. Journal of Experimental Medicine, 203, 1117-1127.
http://dx.doi.org/10.1084/jem.20052321

[88]   Niki, E. (2011) Do free radicals play causal role in atherosclerosis? Low density lipoprotein oxidation and vitamin E revisited. Journal of Clinical Biochemistry and Nutrition, 48, 3-7. http://dx.doi.org/10.3164/jcbn.11-007FR

[89]   Podmore, I.D., Griffiths, H.R., Herbert, K.E., Mistry, N., Mistry, P. and Lunec, J. (1998) Vitamin C exhibits prooxidant properties. Nature, 392, 559.
http://dx.doi.org/10.1038/33308

[90]   Nyyssonen, K., Porkkala Sarataho, E., Kaikkonen, J. and Salonen, J.T. (1997) Ascorbate and urate are the strongest determinants of plasma antioxidative capacity and serum lipid resistance to oxidation in Finnish men. Atherosclerosis, 130, 223-233.
http://dx.doi.org/10.1016/S0021-9150(96)06064-9

[91]   Bowry, V.W. and Stocker, R. (1993) Tocopherol-mediated peroxidation. The prooxidant effect of vitamin E on the radical-initiated oxidation of human low-density-lipoprotein. Journal of the American Chemical Society, 115, 6029-6044. http://dx.doi.org/10.1021/ja00067a019

[92]   Koshkaryev, A., Barshtein, G. and Yedgar, S. (2010) Vitamin E. induces phosphatidylserine externalization and red cell adhesion to endothelial cells. Cell Biochemistry and Biophysics, 56, 109-114.
http://dx.doi.org/10.1007/s12013-009-9074-3

[93]   Manea, A. (2012) Vascular biology of reactive oxygen species and NADPH oxidases: Role in atherogenesis. In: Parthasarathy, S., Ed., Atherogenesis, InTech, 425-446.
http://dx.doi.org/10.5772/25368

[94]   Lichtenberg, D. (2011) Who is likely to gain from high dose supplementation of vitamin E? Harefuah (heb), 150, 37-40.

[95]   Witztum, J.L. (1998) To E or not to E—How do we tell? Circulation, 98, 2785-2787.
http://dx.doi.org/10.1161/01.CIR.98.25.2785

[96]   Frei, B. (2003) To C or not to C, that is the question! Journal of the American College of Cardiology, 42, 253-255.
http://dx.doi.org/10.1016/S0735-1097(03)00574-6

[97]   Boaz, M., Smetana, S., Weinstein, T., Matas, Z., Gafter, U., Iaina, A., et al. (2000) Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): Randomised placebo-controlled trial. Lancet, 356, 1213-1218.
http://dx.doi.org/10.1016/S0140-6736(00)02783-5

[98]   Blum, S., Vardi, M., Brown, J.B., Russell, A., Milman, U., Shapira, C., Levy, N.S., Miller-Lotan, R., Asleh, R. and Levy, A.P. (2010) Vitamin E reduces cardiovascular disease in individuals with diabetes mellitus and the haptoglobin 2-2 genotype. Pharmacogenomics, 11, 675-684.
http://dx.doi.org/10.2217/pgs.10.17

[99]   Lloret, A., Badia, M.C., Mora, N.J., Pallardo, F.V., Alonso, M.D. and Vina, J. (2009) Vitamin E paradox in Alzheimer’s disease: It does not prevent loss of cognition and may even be detrimental. Journal of Alzheimer’s Disease, 17, 143-149.

[100]   Kanner, J., Gorelik, S., Roman, S. and Kohen, R. (2012) Protection by polyphenols of postprandial human plasma and low-density lipoprotein modification: The stomach as a bioreactor. Journal of Agricultural and Food Chemistry, 60, 8790-8796. http://dx.doi.org/10.1021/jf300193g

 
 
Top