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J Clin Invest. Oct 1989; 84(4): 1086–1095.
PMCID: PMC329764

Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man.


Three lines of evidence are presented that low density lipoproteins gently extracted from human and rabbit atherosclerotic lesions (lesion LDL) greatly resembles LDL that has been oxidatively modified in vitro. First, lesion LDL showed many of the physical and chemical properties of oxidized LDL, properties that differ from those of plasma LDL: higher electrophoretic mobility, a higher density, higher free cholesterol content, and a higher proportion of sphingomyelin and lysophosphatidylcholine in the phospholipid fraction. A number of lower molecular weight fragments of apo B were found in lesion LDL, similar to in vitro oxidized LDL. Second, both the intact apo B and some of the apo B fragments of lesion LDL reacted in Western blots with antisera that recognize malondialdehyde-conjugated lysine and 4-hydroxynonenal lysine adducts, both of which are found in oxidized LDL; plasma LDL and LDL from normal human intima showed no such reactivity. Third, lesion LDL shared biological properties with oxidized LDL: compared with plasma LDL, lesion LDL produced much greater stimulation of cholesterol esterification and was degraded more rapidly by macrophages. Degradation of radiolabeled lesion LDL was competitively inhibited by unlabeled lesion LDL, by LDL oxidized with copper, by polyinosinic acid and by malondialdehyde-LDL, but not by native LDL, indicating uptake by the scavenger receptor(s). Finally, lesion LDL (but not normal intimal LDL or plasma LDL) was chemotactic for monocytes, as is oxidized LDL. These studies provide strong evidence that atherosclerotic lesions, both in man and in rabbit, contain oxidatively modified LDL.

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  • Smith EB. The relationship between plasma and tissue lipids in human atherosclerosis. Adv Lipid Res. 1974;12(0):1–49. [PubMed]
  • Schaffner T, Taylor K, Bartucci EJ, Fischer-Dzoga K, Beeson JH, Glagov S, Wissler RW. Arterial foam cells with distinctive immunomorphologic and histochemical features of macrophages. Am J Pathol. 1980 Jul;100(1):57–80. [PMC free article] [PubMed]
  • Gerrity RG. The role of the monocyte in atherogenesis: I. Transition of blood-borne monocytes into foam cells in fatty lesions. Am J Pathol. 1981 May;103(2):181–190. [PMC free article] [PubMed]
  • Faggiotto A, Ross R, Harker L. Studies of hypercholesterolemia in the nonhuman primate. I. Changes that lead to fatty streak formation. Arteriosclerosis. 1984 Jul-Aug;4(4):323–340. [PubMed]
  • Goldstein JL, Ho YK, Basu SK, Brown MS. Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proc Natl Acad Sci U S A. 1979 Jan;76(1):333–337. [PMC free article] [PubMed]
  • Mahley RW, Innerarity TL, Weisgraber KB, Oh SY. Altered metabolism (in vivo and in vitro) of plasma lipoproteins after selective chemical modification of lysine residues of the apoproteins. J Clin Invest. 1979 Sep;64(3):743–750. [PMC free article] [PubMed]
  • Fogelman AM, Shechter I, Seager J, Hokom M, Child JS, Edwards PA. Malondialdehyde alteration of low density lipoproteins leads to cholesteryl ester accumulation in human monocyte-macrophages. Proc Natl Acad Sci U S A. 1980 Apr;77(4):2214–2218. [PMC free article] [PubMed]
  • Henriksen T, Mahoney EM, Steinberg D. Enhanced macrophage degradation of low density lipoprotein previously incubated with cultured endothelial cells: recognition by receptors for acetylated low density lipoproteins. Proc Natl Acad Sci U S A. 1981 Oct;78(10):6499–6503. [PMC free article] [PubMed]
  • Henriksen T, Mahoney EM, Steinberg D. Interactions of plasma lipoproteins with endothelial cells. Ann N Y Acad Sci. 1982;401:102–116. [PubMed]
  • Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL, Steinberg D. Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. Proc Natl Acad Sci U S A. 1984 Jun;81(12):3883–3887. [PMC free article] [PubMed]
  • Heinecke JW, Baker L, Rosen H, Chait A. Superoxide-mediated modification of low density lipoprotein by arterial smooth muscle cells. J Clin Invest. 1986 Mar;77(3):757–761. [PMC free article] [PubMed]
  • Parthasarathy S, Printz DJ, Boyd D, Joy L, Steinberg D. Macrophage oxidation of low density lipoprotein generates a modified form recognized by the scavenger receptor. Arteriosclerosis. 1986 Sep-Oct;6(5):505–510. [PubMed]
  • Carew TE, Schwenke DC, Steinberg D. 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. Proc Natl Acad Sci U S A. 1987 Nov;84(21):7725–7729. [PMC free article] [PubMed]
  • Kita T, Nagano Y, Yokode M, Ishii K, Kume N, Ooshima A, Yoshida H, Kawai C. Probucol prevents the progression of atherosclerosis in Watanabe heritable hyperlipidemic rabbit, an animal model for familial hypercholesterolemia. Proc Natl Acad Sci U S A. 1987 Aug;84(16):5928–5931. [PMC free article] [PubMed]
  • Haberland ME, Fong D, Cheng L. Malondialdehyde-altered protein occurs in atheroma of Watanabe heritable hyperlipidemic rabbits. Science. 1988 Jul 8;241(4862):215–218. [PubMed]
  • Palinski W, Rosenfeld ME, Ylä-Herttuala S, Gurtner GC, Socher SS, Butler SW, Parthasarathy S, Carew TE, Steinberg D, Witztum JL. Low density lipoprotein undergoes oxidative modification in vivo. Proc Natl Acad Sci U S A. 1989 Feb;86(4):1372–1376. [PMC free article] [PubMed]
  • Hollander W, Paddock J, Colombo M. Lipoproteins in human atherosclerotic vessels. I. Biochemical properties of arterial low density lipoproteins, very low density lipoproteins, and high density lipoproteins. Exp Mol Pathol. 1979 Apr;30(2):144–171. [PubMed]
  • Goldstein JL, Hoff HF, Ho YK, Basu SK, Brown MS. Stimulation of cholesteryl ester synthesis in macrophages by extracts of atherosclerotic human aortas and complexes of albumin/cholesteryl esters. Arteriosclerosis. 1981 May-Jun;1(3):210–226. [PubMed]
  • Hoff HF, Gaubatz JW. Isolation, purification, and characterization of a lipoprotein containing Apo B from the human aorta. Atherosclerosis. 1982 Apr;42(2-3):273–297. [PubMed]
  • Clevidence BA, Morton RE, West G, Dusek DM, Hoff HF. Cholesterol esterification in macrophages. Stimulation by lipoproteins containing apo B isolated from human aortas. Arteriosclerosis. 1984 May-Jun;4(3):196–207. [PubMed]
  • Morton RE, West GA, Hoff HF. A low density lipoprotein-sized particle isolated from human atherosclerotic lesions is internalized by macrophages via a non-scavenger-receptor mechanism. J Lipid Res. 1986 Nov;27(11):1124–1134. [PubMed]
  • Ylä-Herttuala S, Jaakkola O, Ehnholm C, Tikkanen MJ, Solakivi T, Särkioja T, Nikkari T. Characterization of two lipoproteins containing apolipoproteins B and E from lesion-free human aortic intima. J Lipid Res. 1988 May;29(5):563–572. [PubMed]
  • Shaikh M, Martini S, Quiney JR, Baskerville P, La Ville AE, Browse NL, Duffield R, Turner PR, Lewis B. Modified plasma-derived lipoproteins in human atherosclerotic plaques. Atherosclerosis. 1988 Feb;69(2-3):165–172. [PubMed]
  • Daugherty A, Zweifel BS, Sobel BE, Schonfeld G. Isolation of low density lipoprotein from atherosclerotic vascular tissue of Watanabe heritable hyperlipidemic rabbits. Arteriosclerosis. 1988 Nov-Dec;8(6):768–777. [PubMed]
  • Jürgens G, Lang J, Esterbauer H. Modification of human low-density lipoprotein by the lipid peroxidation product 4-hydroxynonenal. Biochim Biophys Acta. 1986 Jan 3;875(1):103–114. [PubMed]
  • Esterbauer H, Jürgens G, Quehenberger O, Koller E. Autoxidation of human low density lipoprotein: loss of polyunsaturated fatty acids and vitamin E and generation of aldehydes. J Lipid Res. 1987 May;28(5):495–509. [PubMed]
  • Steinbrecher UP, Witztum JL, 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. [PubMed]
  • Steinbrecher UP. Oxidation of human low density lipoprotein results in derivatization of lysine residues of apolipoprotein B by lipid peroxide decomposition products. J Biol Chem. 1987 Mar 15;262(8):3603–3608. [PubMed]
  • Schuh J, Fairclough GF, Jr, Haschemeyer RH. Oxygen-mediated heterogeneity of apo-low-density lipoprotein. Proc Natl Acad Sci U S A. 1978 Jul;75(7):3173–3177. [PMC free article] [PubMed]
  • Lee DM, Valente AJ, Kuo WH, Maeda H. Properties of apolipoprotein B in urea and in aqueous buffers. The use of glutathione and nitrogen in its solubilization. Biochim Biophys Acta. 1981 Oct 23;666(1):133–146. [PubMed]
  • Khoo JC, Miller E, McLoughlin P, Steinberg D. Enhanced macrophage uptake of low density lipoprotein after self-aggregation. Arteriosclerosis. 1988 Jul-Aug;8(4):348–358. [PubMed]
  • HAVEL RJ, EDER HA, BRAGDON JH. The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J Clin Invest. 1955 Sep;34(9):1345–1353. [PMC free article] [PubMed]
  • LOWRY OH, ROSEBROUGH NJ, FARR AL, RANDALL RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed]
  • Jung DH, Biggs HG, Moorehead WR. Colorimetry of serum cholesterol with use of ferric acetate/uranyl acetate and ferrous sulfate/sulfuric acid reagents. Clin Chem. 1975 Sep;21(10):1526–1530. [PubMed]
  • Young SG, Smith RS, Hogle DM, Curtiss LK, Witztum JL. Two new monoclonal antibody-based enzyme-linked assays of apolipoprotein B. Clin Chem. 1986 Aug;32(8):1484–1490. [PubMed]
  • Young SG, Bertics SJ, Scott TM, Dubois BW, Curtiss LK, Witztum JL. Parallel expression of the MB19 genetic polymorphism in apoprotein B-100 and apoprotein B-48. Evidence that both apoproteins are products of the same gene. J Biol Chem. 1986 Mar 5;261(7):2995–2998. [PubMed]
  • Young SG, Witztum JL, Casal DC, Curtiss LK, 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. [PubMed]
  • Curtiss LK, Edgington TS. Immunochemical heterogeneity of human plasma apolipoprotein B. I. Apolipoprotein B binding of mouse hybridoma antibodies. J Biol Chem. 1982 Dec 25;257(24):15213–15221. [PubMed]
  • Curtiss LK, Witztum JL. 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. [PMC free article] [PubMed]
  • Fong LG, Parthasarathy S, Witztum JL, Steinberg D. Nonenzymatic oxidative cleavage of peptide bonds in apoprotein B-100. J Lipid Res. 1987 Dec;28(12):1466–1477. [PubMed]
  • Basu SK, Goldstein JL, Anderson GW, Brown MS. Degradation of cationized low density lipoprotein and regulation of cholesterol metabolism in homozygous familial hypercholesterolemia fibroblasts. Proc Natl Acad Sci U S A. 1976 Sep;73(9):3178–3182. [PMC free article] [PubMed]
  • Salacinski PR, McLean C, Sykes JE, Clement-Jones VV, Lowry PJ. Iodination of proteins, glycoproteins, and peptides using a solid-phase oxidizing agent, 1,3,4,6-tetrachloro-3 alpha,6 alpha-diphenyl glycoluril (Iodogen). Anal Biochem. 1981 Oct;117(1):136–146. [PubMed]
  • Weinstein DB, Carew TE, Steinberg D. Uptake and degradation of low density lipoprotein by swine arterial smoot muscle cells with inhibition of cholesterol biosynthesis. Biochim Biophys Acta. 1976 Mar 26;424(3):404–421. [PubMed]
  • Goldstein JL, Basu SK, Brown MS. Receptor-mediated endocytosis of low-density lipoprotein in cultured cells. Methods Enzymol. 1983;98:241–260. [PubMed]
  • Quinn MT, Parthasarathy S, Fong LG, Steinberg D. Oxidatively modified low density lipoproteins: a potential role in recruitment and retention of monocyte/macrophages during atherogenesis. Proc Natl Acad Sci U S A. 1987 May;84(9):2995–2998. [PMC free article] [PubMed]
  • Quinn MT, Parthasarathy S, Steinberg D. Lysophosphatidylcholine: a chemotactic factor for human monocytes and its potential role in atherogenesis. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2805–2809. [PMC free article] [PubMed]
  • Sparrow CP, Parthasarathy S, Steinberg D. A macrophage receptor that recognizes oxidized low density lipoprotein but not acetylated low density lipoprotein. J Biol Chem. 1989 Feb 15;264(5):2599–2604. [PubMed]
  • Arai H, Kita T, Yokode M, Narumiya S, Kawai C. Multiple receptors for modified low density lipoproteins in mouse peritoneal macrophages: different uptake mechanisms for acetylated and oxidized low density lipoproteins. Biochem Biophys Res Commun. 1989 Mar 31;159(3):1375–1382. [PubMed]
  • Parthasarathy S, Steinbrecher UP, Barnett J, Witztum JL, Steinberg D. Essential role of phospholipase A2 activity in endothelial cell-induced modification of low density lipoprotein. Proc Natl Acad Sci U S A. 1985 May;82(9):3000–3004. [PMC free article] [PubMed]

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