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. 1996 Aug 1;98(3):800–814. doi: 10.1172/JCI118853

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.

W Palinski 1, S Hörkkö 1, E Miller 1, U P Steinbrecher 1, H C Powell 1, L K Curtiss 1, J L Witztum 1
PMCID: PMC507491  PMID: 8698873

Abstract

Many reactive products may be formed when LDL undergoes lipid peroxidation, which in turn can react with lipids, apoproteins, and proteins, generating immunogenic neoepitopes. Autoantibodies recognizing model epitopes of oxidized low density lipoprotein, such as malondialdehydelysine, occur in plasma and in atherosclerotic lesions of humans and animals. Because apo E-deficient mice develop particularly high titers of such autoantibodies, we used their spleens to clone 13 monoclonal antibodies to various epitopes of oxidized LDL ("E0 antibodies"). Binding and competitive RIAs demonstrated significant differences in fine specificity even between E0 antibodies initially selected for binding to the same screening antigen. For example, some E0 antibodies selected for binding to malondialdehyde-LDL also recognized copper oxidized LDL, acrolein-LDL, or LDL modified by arachidonic or linoleic acid oxidation products. Circulating IgG and IgM autoantibodies binding to copper-oxidized LDL, 4-hydroxynonenal-LDL, acrolein-LDL, and LDL modified with arachidonic or linoleic acid oxidation products were found in apo E-deficient mice, suggesting that the respective antigens are formed in vivo. Epitopes recognized by some of the E0 monoclonal antibodies were also found on human circulating LDL. Each of the E0 monoclonal antibodies immunostained rabbit and human atherosclerotic lesions, and some of them yielded distinct staining patterns in advanced lesions. Together, this suggests that the natural monoclonal antibodies recognize different epitopes of complex structures formed during oxidation of lipoproteins, or epitopes formed independently at different lesion sites. Our data demonstrate that a profound immunological response to a large number of different epitopes of oxidized lipoproteins occurs in vivo. The availability of "natural" monoclonal autoantibodies should facilitate the identification of specific epitopes inducing this response.

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Selected References

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  1. Armstrong V. W., Wieland E., Diedrich F., Renner A., Rath W., Kreuzer H., Kuhn W., Oellerich M. Serum antibodies to oxidised low-density lipoprotein in pre-eclampsia and coronary heart disease. Lancet. 1994 Jun 18;343(8912):1570–1570. doi: 10.1016/s0140-6736(94)92971-8. [DOI] [PubMed] [Google Scholar]
  2. Bellomo G., Maggi E., Poli M., Agosta F. G., Bollati P., Finardi G. Autoantibodies against oxidatively modified low-density lipoproteins in NIDDM. Diabetes. 1995 Jan;44(1):60–66. doi: 10.2337/diab.44.1.60. [DOI] [PubMed] [Google Scholar]
  3. Bergmark C., Wu R., de Faire U., Lefvert A. K., Swedenborg J. Patients with early-onset peripheral vascular disease have increased levels of autoantibodies against oxidized LDL. Arterioscler Thromb Vasc Biol. 1995 Apr;15(4):441–445. doi: 10.1161/01.atv.15.4.441. [DOI] [PubMed] [Google Scholar]
  4. Berliner J. A., Navab M., Fogelman A. M., Frank J. S., Demer L. L., Edwards P. A., Watson A. D., Lusis A. J. Atherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics. Circulation. 1995 May 1;91(9):2488–2496. doi: 10.1161/01.cir.91.9.2488. [DOI] [PubMed] [Google Scholar]
  5. Boyd H. C., Gown A. M., Wolfbauer G., Chait A. Direct evidence for a protein recognized by a monoclonal antibody against oxidatively modified LDL in atherosclerotic lesions from a Watanabe heritable hyperlipidemic rabbit. Am J Pathol. 1989 Nov;135(5):815–825. [PMC free article] [PubMed] [Google Scholar]
  6. Branch D. W., Mitchell M. D., Miller E., Palinski W., Witztum J. L. Pre-eclampsia and serum antibodies to oxidised low-density lipoprotein. Lancet. 1994 Mar 12;343(8898):645–646. doi: 10.1016/s0140-6736(94)92639-5. [DOI] [PubMed] [Google Scholar]
  7. Chisolm G. M., Ma G., Irwin K. C., Martin L. L., Gunderson K. G., Linberg L. F., Morel D. W., DiCorleto P. E. 7 beta-hydroperoxycholest-5-en-3 beta-ol, a component of human atherosclerotic lesions, is the primary cytotoxin of oxidized human low density lipoprotein. Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11452–11456. doi: 10.1073/pnas.91.24.11452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Coffey M. D., Cole R. A., Colles S. M., Chisolm G. M. In vitro cell injury by oxidized low density lipoprotein involves lipid hydroperoxide-induced formation of alkoxyl, lipid, and peroxyl radicals. J Clin Invest. 1995 Oct;96(4):1866–1873. doi: 10.1172/JCI118232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Coppola G., Underwood J., Cartwright G., Hearn M. T. High-performance liquid chromatography of amino acids, peptides and proteins. XCIII. Comparison of methods for the purification of mouse monoclonal immunoglobulin M autoantibodies. J Chromatogr. 1989 Aug 4;476:269–290. doi: 10.1016/s0021-9673(01)93875-0. [DOI] [PubMed] [Google Scholar]
  10. Curtiss L. K., Witztum J. L. A novel method for generating region-specific monoclonal antibodies to modified proteins. Application to the identification of human glucosylated low density lipoproteins. J Clin Invest. 1983 Oct;72(4):1427–1438. doi: 10.1172/JCI111099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Daugherty A., Dunn J. L., Rateri D. L., Heinecke J. W. Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions. J Clin Invest. 1994 Jul;94(1):437–444. doi: 10.1172/JCI117342. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Esterbauer H., Gebicki J., Puhl H., Jürgens G. The role of lipid peroxidation and antioxidants in oxidative modification of LDL. Free Radic Biol Med. 1992 Oct;13(4):341–390. doi: 10.1016/0891-5849(92)90181-f. [DOI] [PubMed] [Google Scholar]
  13. Esterbauer H., Schaur R. J., Zollner H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med. 1991;11(1):81–128. doi: 10.1016/0891-5849(91)90192-6. [DOI] [PubMed] [Google Scholar]
  14. Fyfe A. I., Qiao J. H., Lusis A. J. Immune-deficient mice develop typical atherosclerotic fatty streaks when fed an atherogenic diet. J Clin Invest. 1994 Dec;94(6):2516–2520. doi: 10.1172/JCI117622. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gown A. M., Tsukada T., Ross R. Human atherosclerosis. II. Immunocytochemical analysis of the cellular composition of human atherosclerotic lesions. Am J Pathol. 1986 Oct;125(1):191–207. [PMC free article] [PubMed] [Google Scholar]
  16. Gown A. M., Vogel A. M., Gordon D., Lu P. L. A smooth muscle-specific monoclonal antibody recognizes smooth muscle actin isozymes. J Cell Biol. 1985 Mar;100(3):807–813. doi: 10.1083/jcb.100.3.807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Habeeb A. F. Chemical evaluation of conformational differences in native and chemically modified proteins. Biochim Biophys Acta. 1966 Feb 28;115(2):440–454. doi: 10.1016/0304-4165(66)90442-9. [DOI] [PubMed] [Google Scholar]
  18. Haberland M. E., Fong D., Cheng L. Malondialdehyde-altered protein occurs in atheroma of Watanabe heritable hyperlipidemic rabbits. Science. 1988 Jul 8;241(4862):215–218. doi: 10.1126/science.2455346. [DOI] [PubMed] [Google Scholar]
  19. Hammer A., Kager G., Dohr G., Rabl H., Ghassempur I., Jürgens G. Generation, characterization, and histochemical application of monoclonal antibodies selectively recognizing oxidatively modified apoB-containing serum lipoproteins. Arterioscler Thromb Vasc Biol. 1995 May;15(5):704–713. doi: 10.1161/01.atv.15.5.704. [DOI] [PubMed] [Google Scholar]
  20. Hansson G. K., Holm J., Holm S., Fotev Z., Hedrich H. J., Fingerle J. T lymphocytes inhibit the vascular response to injury. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10530–10534. doi: 10.1073/pnas.88.23.10530. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Heery J. M., Kozak M., Stafforini D. M., Jones D. A., Zimmerman G. A., McIntyre T. M., Prescott S. M. Oxidatively modified LDL contains phospholipids with platelet-activating factor-like activity and stimulates the growth of smooth muscle cells. J Clin Invest. 1995 Nov;96(5):2322–2330. doi: 10.1172/JCI118288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Heitzer T., Ylä-Herttuala S., Luoma J., Kurz S., Münzel T., Just H., Olschewski M., Drexler H. Cigarette smoking potentiates endothelial dysfunction of forearm resistance vessels in patients with hypercholesterolemia. Role of oxidized LDL. Circulation. 1996 Apr 1;93(7):1346–1353. doi: 10.1161/01.cir.93.7.1346. [DOI] [PubMed] [Google Scholar]
  23. Hodis H. N., Kramsch D. M., Avogaro P., Bittolo-Bon G., Cazzolato G., Hwang J., Peterson H., Sevanian A. Biochemical and cytotoxic characteristics of an in vivo circulating oxidized low density lipoprotein (LDL-). J Lipid Res. 1994 Apr;35(4):669–677. [PubMed] [Google Scholar]
  24. Hoff H. F., O'Neil J. Structural and functional changes in LDL after modification with both 4-hydroxynonenal and malondialdehyde. J Lipid Res. 1993 Jul;34(7):1209–1217. [PubMed] [Google Scholar]
  25. Holvoet P., Perez G., Zhao Z., Brouwers E., Bernar H., Collen D. Malondialdehyde-modified low density lipoproteins in patients with atherosclerotic disease. J Clin Invest. 1995 Jun;95(6):2611–2619. doi: 10.1172/JCI117963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Houglum K., Filip M., Witztum J. L., Chojkier M. Malondialdehyde and 4-hydroxynonenal protein adducts in plasma and liver of rats with iron overload. J Clin Invest. 1990 Dec;86(6):1991–1998. doi: 10.1172/JCI114934. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Huang Y. H., Rönnelid J., Frostegård J. Oxidized LDL induces enhanced antibody formation and MHC class II-dependent IFN-gamma production in lymphocytes from healthy individuals. Arterioscler Thromb Vasc Biol. 1995 Oct;15(10):1577–1583. doi: 10.1161/01.atv.15.10.1577. [DOI] [PubMed] [Google Scholar]
  28. Hörkkö S., Miller E., Dudl E., Reaven P., Curtiss L. K., Zvaifler N. J., Terkeltaub R., Pierangeli S. S., Branch D. W., Palinski W. Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids. Recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein. J Clin Invest. 1996 Aug 1;98(3):815–825. doi: 10.1172/JCI118854. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Ishibashi S., Brown M. S., Goldstein J. L., Gerard R. D., Hammer R. E., Herz J. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J Clin Invest. 1993 Aug;92(2):883–893. doi: 10.1172/JCI116663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Ishibashi S., Goldstein J. L., Brown M. S., Herz J., Burns D. K. Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice. J Clin Invest. 1994 May;93(5):1885–1893. doi: 10.1172/JCI117179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Itabe H., Takeshima E., Iwasaki H., Kimura J., Yoshida Y., Imanaka T., Takano T. A monoclonal antibody against oxidized lipoprotein recognizes foam cells in atherosclerotic lesions. Complex formation of oxidized phosphatidylcholines and polypeptides. J Biol Chem. 1994 May 27;269(21):15274–15279. [PubMed] [Google Scholar]
  32. Itabe H., Yamamoto H., Imanaka T., Shimamura K., Uchiyama H., Kimura J., Sanaka T., Hata Y., Takano T. Sensitive detection of oxidatively modified low density lipoprotein using a monoclonal antibody. J Lipid Res. 1996 Jan;37(1):45–53. [PubMed] [Google Scholar]
  33. Liao F., Andalibi A., deBeer F. C., Fogelman A. M., Lusis A. J. Genetic control of inflammatory gene induction and NF-kappa B-like transcription factor activation in response to an atherogenic diet in mice. J Clin Invest. 1993 Jun;91(6):2572–2579. doi: 10.1172/JCI116495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Maggi E., Chiesa R., Melissano G., Castellano R., Astore D., Grossi A., Finardi G., Bellomo G. LDL oxidation in patients with severe carotid atherosclerosis. A study of in vitro and in vivo oxidation markers. Arterioscler Thromb. 1994 Dec;14(12):1892–1899. doi: 10.1161/01.atv.14.12.1892. [DOI] [PubMed] [Google Scholar]
  35. Maggi E., Finardi G., Poli M., Bollati P., Filipponi M., Stefano P. L., Paolini G., Grossi A., Clot P., Albano E. Specificity of autoantibodies against oxidized LDL as an additional marker for atherosclerotic risk. Coron Artery Dis. 1993 Dec;4(12):1119–1122. doi: 10.1097/00019501-199312000-00014. [DOI] [PubMed] [Google Scholar]
  36. Malle E., Hazell L., Stocker R., Sattler W., Esterbauer H., Waeg G. Immunologic detection and measurement of hypochlorite-modified LDL with specific monoclonal antibodies. Arterioscler Thromb Vasc Biol. 1995 Jul;15(7):982–989. doi: 10.1161/01.atv.15.7.982. [DOI] [PubMed] [Google Scholar]
  37. Nakashima Y., Plump A. S., Raines E. W., Breslow J. L., Ross R. ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler Thromb. 1994 Jan;14(1):133–140. doi: 10.1161/01.atv.14.1.133. [DOI] [PubMed] [Google Scholar]
  38. Neale T. J., Ojha P. P., Exner M., Poczewski H., Rüger B., Witztum J. L., Davis P., Kerjaschki D. Proteinuria in passive Heymann nephritis is associated with lipid peroxidation and formation of adducts on type IV collagen. J Clin Invest. 1994 Oct;94(4):1577–1584. doi: 10.1172/JCI117499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Newcombe J., Li H., Cuzner M. L. Low density lipoprotein uptake by macrophages in multiple sclerosis plaques: implications for pathogenesis. Neuropathol Appl Neurobiol. 1994 Apr;20(2):152–162. doi: 10.1111/j.1365-2990.1994.tb01174.x. [DOI] [PubMed] [Google Scholar]
  40. Ohara Y., Peterson T. E., Harrison D. G. Hypercholesterolemia increases endothelial superoxide anion production. J Clin Invest. 1993 Jun;91(6):2546–2551. doi: 10.1172/JCI116491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Orekhov A. N., Tertov V. V., Kabakov A. E., Adamova IYu, Pokrovsky S. N., Smirnov V. N. Autoantibodies against modified low density lipoprotein. Nonlipid factor of blood plasma that stimulates foam cell formation. Arterioscler Thromb. 1991 Mar-Apr;11(2):316–326. doi: 10.1161/01.atv.11.2.316. [DOI] [PubMed] [Google Scholar]
  42. Palinski W., Miller E., Witztum J. L. Immunization of low density lipoprotein (LDL) receptor-deficient rabbits with homologous malondialdehyde-modified LDL reduces atherogenesis. Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):821–825. doi: 10.1073/pnas.92.3.821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Palinski W., Ord V. A., Plump A. S., Breslow J. L., Steinberg D., Witztum J. L. ApoE-deficient mice are a model of lipoprotein oxidation in atherogenesis. Demonstration of oxidation-specific epitopes in lesions and high titers of autoantibodies to malondialdehyde-lysine in serum. Arterioscler Thromb. 1994 Apr;14(4):605–616. doi: 10.1161/01.atv.14.4.605. [DOI] [PubMed] [Google Scholar]
  44. Palinski W., Rosenfeld M. E., Ylä-Herttuala S., Gurtner G. C., Socher S. S., Butler S. W., Parthasarathy S., Carew T. E., Steinberg D., Witztum J. L. Low density lipoprotein undergoes oxidative modification in vivo. Proc Natl Acad Sci U S A. 1989 Feb;86(4):1372–1376. doi: 10.1073/pnas.86.4.1372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Palinski W., Tangirala R. K., Miller E., Young S. G., Witztum J. L. Increased autoantibody titers against epitopes of oxidized LDL in LDL receptor-deficient mice with increased atherosclerosis. Arterioscler Thromb Vasc Biol. 1995 Oct;15(10):1569–1576. doi: 10.1161/01.atv.15.10.1569. [DOI] [PubMed] [Google Scholar]
  46. Palinski W., Ylä-Herttuala S., Rosenfeld M. E., Butler S. W., Socher S. A., Parthasarathy S., Curtiss L. K., Witztum J. L. Antisera and monoclonal antibodies specific for epitopes generated during oxidative modification of low density lipoprotein. Arteriosclerosis. 1990 May-Jun;10(3):325–335. doi: 10.1161/01.atv.10.3.325. [DOI] [PubMed] [Google Scholar]
  47. Parums D. V., Brown D. L., Mitchinson M. J. Serum antibodies to oxidized low-density lipoprotein and ceroid in chronic periaortitis. Arch Pathol Lab Med. 1990 Apr;114(4):383–387. [PubMed] [Google Scholar]
  48. Plump A. S., Smith J. D., Hayek T., Aalto-Setälä K., Walsh A., Verstuyft J. G., Rubin E. M., Breslow J. L. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell. 1992 Oct 16;71(2):343–353. doi: 10.1016/0092-8674(92)90362-g. [DOI] [PubMed] [Google Scholar]
  49. Puurunen M., Mänttäri M., Manninen V., Tenkanen L., Alfthan G., Ehnholm C., Vaarala O., Aho K., Palosuo T. Antibody against oxidized low-density lipoprotein predicting myocardial infarction. Arch Intern Med. 1994 Nov 28;154(22):2605–2609. [PubMed] [Google Scholar]
  50. Reddick R. L., Zhang S. H., Maeda N. Atherosclerosis in mice lacking apo E. Evaluation of lesional development and progression. Arterioscler Thromb. 1994 Jan;14(1):141–147. doi: 10.1161/01.atv.14.1.141. [DOI] [PubMed] [Google Scholar]
  51. Roselaar S. E., Schonfeld G., Daugherty A. Enhanced development of atherosclerosis in cholesterol-fed rabbits by suppression of cell-mediated immunity. J Clin Invest. 1995 Sep;96(3):1389–1394. doi: 10.1172/JCI118174. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Rosenfeld M. E., Khoo J. C., Miller E., Parthasarathy S., Palinski W., Witztum J. L. Macrophage-derived foam cells freshly isolated from rabbit atherosclerotic lesions degrade modified lipoproteins, promote oxidation of low-density lipoproteins, and contain oxidation-specific lipid-protein adducts. J Clin Invest. 1991 Jan;87(1):90–99. doi: 10.1172/JCI115006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Rosenfeld M. E., Palinski W., Ylä-Herttuala S., Butler S., Witztum J. L. Distribution of oxidation specific lipid-protein adducts and apolipoprotein B in atherosclerotic lesions of varying severity from WHHL rabbits. Arteriosclerosis. 1990 May-Jun;10(3):336–349. doi: 10.1161/01.atv.10.3.336. [DOI] [PubMed] [Google Scholar]
  54. Salonen J. T., Ylä-Herttuala S., Yamamoto R., Butler S., Korpela H., Salonen R., Nyyssönen K., Palinski W., Witztum J. L. Autoantibody against oxidised LDL and progression of carotid atherosclerosis. Lancet. 1992 Apr 11;339(8798):883–887. doi: 10.1016/0140-6736(92)90926-t. [DOI] [PubMed] [Google Scholar]
  55. Steinberg D., Parthasarathy S., Carew T. E., Khoo J. C., Witztum J. L. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989 Apr 6;320(14):915–924. doi: 10.1056/NEJM198904063201407. [DOI] [PubMed] [Google Scholar]
  56. Steinbrecher U. P., Lougheed M., Kwan W. C., Dirks M. Recognition of oxidized low density lipoprotein by the scavenger receptor of macrophages results from derivatization of apolipoprotein B by products of fatty acid peroxidation. J Biol Chem. 1989 Sep 15;264(26):15216–15223. [PubMed] [Google Scholar]
  57. Steinbrecher U. P., Witztum J. L., Parthasarathy S., Steinberg D. Decrease in reactive amino groups during oxidation or endothelial cell modification of LDL. Correlation with changes in receptor-mediated catabolism. Arteriosclerosis. 1987 Mar-Apr;7(2):135–143. doi: 10.1161/01.atv.7.2.135. [DOI] [PubMed] [Google Scholar]
  58. Stemme S., Faber B., Holm J., Wiklund O., Witztum J. L., Hansson G. K. T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3893–3897. doi: 10.1073/pnas.92.9.3893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Tangirala R. K., Rubin E. M., Palinski W. Quantitation of atherosclerosis in murine models: correlation between lesions in the aortic origin and in the entire aorta, and differences in the extent of lesions between sexes in LDL receptor-deficient and apolipoprotein E-deficient mice. J Lipid Res. 1995 Nov;36(11):2320–2328. [PubMed] [Google Scholar]
  60. Virella G., Virella I., Leman R. B., Pryor M. B., Lopes-Virella M. F. Anti-oxidized low-density lipoprotein antibodies in patients with coronary heart disease and normal healthy volunteers. Int J Clin Lab Res. 1993;23(2):95–101. doi: 10.1007/BF02592290. [DOI] [PubMed] [Google Scholar]
  61. Watson A. D., Navab M., Hama S. Y., Sevanian A., Prescott S. M., Stafforini D. M., McIntyre T. M., Du B. N., Fogelman A. M., Berliner J. A. Effect of platelet activating factor-acetylhydrolase on the formation and action of minimally oxidized low density lipoprotein. J Clin Invest. 1995 Feb;95(2):774–782. doi: 10.1172/JCI117726. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Witztum J. L., Steinbrecher U. P., Fisher M., Kesaniemi A. Nonenzymatic glucosylation of homologous low density lipoprotein and albumin renders them immunogenic in the guinea pig. Proc Natl Acad Sci U S A. 1983 May;80(9):2757–2761. doi: 10.1073/pnas.80.9.2757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Witztum J. L. The oxidation hypothesis of atherosclerosis. Lancet. 1994 Sep 17;344(8925):793–795. doi: 10.1016/s0140-6736(94)92346-9. [DOI] [PubMed] [Google Scholar]
  64. Yan S. D., Chen X., Schmidt A. M., Brett J., Godman G., Zou Y. S., Scott C. W., Caputo C., Frappier T., Smith M. A. Glycated tau protein in Alzheimer disease: a mechanism for induction of oxidant stress. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7787–7791. doi: 10.1073/pnas.91.16.7787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Yan S. D., Schmidt A. M., Anderson G. M., Zhang J., Brett J., Zou Y. S., Pinsky D., Stern D. Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins. J Biol Chem. 1994 Apr 1;269(13):9889–9897. [PubMed] [Google Scholar]
  66. Ylä-Herttuala S., Palinski W., Butler S. W., Picard S., Steinberg D., Witztum J. L. Rabbit and human atherosclerotic lesions contain IgG that recognizes epitopes of oxidized LDL. Arterioscler Thromb. 1994 Jan;14(1):32–40. doi: 10.1161/01.atv.14.1.32. [DOI] [PubMed] [Google Scholar]
  67. Ylä-Herttuala S., Palinski W., Rosenfeld M. E., Parthasarathy S., Carew T. E., Butler S., Witztum J. L., Steinberg D. Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J Clin Invest. 1989 Oct;84(4):1086–1095. doi: 10.1172/JCI114271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Young S. G., Smith R. S., Hogle D. M., Curtiss L. K., Witztum J. L. Two new monoclonal antibody-based enzyme-linked assays of apolipoprotein B. Clin Chem. 1986 Aug;32(8):1484–1490. [PubMed] [Google Scholar]
  69. Young S. G., Witztum J. L., Casal D. C., Curtiss L. K., Bernstein S. Conservation of the low density lipoprotein receptor-binding domain of apoprotein B. Demonstration by a new monoclonal antibody, MB47. Arteriosclerosis. 1986 Mar-Apr;6(2):178–188. doi: 10.1161/01.atv.6.2.178. [DOI] [PubMed] [Google Scholar]
  70. Zhang H., Yang Y., Steinbrecher U. P. Structural requirements for the binding of modified proteins to the scavenger receptor of macrophages. J Biol Chem. 1993 Mar 15;268(8):5535–5542. [PubMed] [Google Scholar]
  71. Zhang S. H., Reddick R. L., Piedrahita J. A., Maeda N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science. 1992 Oct 16;258(5081):468–471. doi: 10.1126/science.1411543. [DOI] [PubMed] [Google Scholar]

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