Arteriosclerosis, Vol 10, 336-349, Copyright © 1990 by American Heart Association

ARTICLES

Distribution of oxidation specific lipid-protein adducts and apolipoprotein B in atherosclerotic lesions of varying severity from WHHL rabbits

ME Rosenfeld, W Palinski, S Yla-Herttuala, S Butler and JL Witztum
Department of Medicine, University of California-San Diego, La Jolla 92093.

Antisera and monoclonal antibodies generated against autologous malondialdehyde-conjugated low density lipoprotein (MDA-LDL), 4- hydroxynonenal conjugated LDL (4-HNE-LDL), and the protein fragments of apoprotein B resulting from the copper oxidation of LDL, as well as antibodies against apoprotein B, were used to immunostain atherosclerotic lesions of varying severity from Watanabe heritable hyperlipemic rabbits. In macrophage-rich fatty streaks and transitional lesions, all of the antibodies recognizing oxidation specific epitopes exhibited predominantly cell-associated staining in particulate and annular patterns. This is in contrast to the limited, extracellular, diffuse staining obtained with the antibodies recognizing apoprotein B. In more advanced lesions containing areas with reduced numbers of cells, there was increased extracellular, diffuse staining with the antibodies against oxidation specific epitopes and co-localization with apoprotein B. In addition, there were annular staining patterns associated with the necrotic core and increased staining of intimal and medial smooth muscle cells. We interpret these data as suggesting that in areas of lesions rich in macrophages, LDL is oxidized and taken up by the cells. In more advanced lesions that are relatively devoid of macrophages, both native and oxidized LDL, as well as oxidation products released from dead and decaying cells, are trapped in the matrix, out of reach of those cells capable of accumulating oxidized LDL.

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				M. Seccia, E. Albano, E. Maggi, and G. Bellomo Circulating Autoantibodies Recognizing Peroxidase-Oxidized Low Density Lipoprotein: Evidence for New Antigenic Epitopes Formed In Vivo Independently From Lipid Peroxidation Arterioscler Thromb Vasc Biol, January 1, 1997; 17(1): 134 - 140. [Abstract] [Full Text]

				M. I.J. Uusitupa, L. Niskanen, J. Luoma, P. Vilja, M. Mercuri, R. Rauramaa, and S. Yla-Herttuala Autoantibodies Against Oxidized LDL Do Not Predict Atherosclerotic Vascular Disease in Non–Insulin-Dependent Diabetes Mellitus Arterioscler Thromb Vasc Biol, October 1, 1996; 16(10): 1236 - 1242. [Abstract] [Full Text]

				K. Juul, L. B. Nielsen, K. Munkholm, S. Stender, and B. G. Nordestgaard Oxidation of Plasma Low-Density Lipoprotein Accelerates Its Accumulation and Degradation in the Arterial Wall In Vivo Circulation, October 1, 1996; 94(7): 1698 - 1704. [Abstract] [Full Text]

				S. L. Hazen, F. F. Hsu, K. Duffin, and J. W. Heinecke Molecular Chlorine Generated by the Myeloperoxidase-Hydrogen Peroxide-Chloride System of Phagocytes Converts Low Density Lipoprotein Cholesterol into a Family of Chlorinated Sterols J. Biol. Chem., September 20, 1996; 271(38): 23080 - 23088. [Abstract] [Full Text] [PDF]

				K. D. O'Brien, C. E. Alpers, J. E. Hokanson, S. Wang, and A. Chait Oxidation-Specific Epitopes in Human Coronary Atherosclerosis Are Not Limited to Oxidized Low-Density Lipoprotein Circulation, September 15, 1996; 94(6): 1216 - 1225. [Abstract] [Full Text]

				J. S. Jacob, D. P. Cistola, F. F. Hsu, S. Muzaffar, D. M. Mueller, S. L. Hazen, and J. W. Heinecke Human Phagocytes Employ the Myeloperoxidase-Hydrogen Peroxide System to Synthesize Dityrosine, Trityrosine, Pulcherosine, and Isodityrosine by a Tyrosyl Radical-dependent Pathway J. Biol. Chem., August 16, 1996; 271(33): 19950 - 19956. [Abstract] [Full Text] [PDF]

				C. K. Mukhopadhyay, E. Ehrenwald, and P. L. Fox Ceruloplasmin Enhances Smooth Muscle Cell- and Endothelial Cell-mediated Low Density Lipoprotein Oxidation by a Superoxide-dependent Mechanism J. Biol. Chem., June 21, 1996; 271(25): 14773 - 14778. [Abstract] [Full Text] [PDF]

				M. Lougheed and U. P. Steinbrecher Mechanism of Uptake of Copper-oxidized Low Density Lipoprotein in Macrophages Is Dependent on Its Extent of Oxidation J. Biol. Chem., May 17, 1996; 271(20): 11798 - 11805. [Abstract] [Full Text] [PDF]

				K. D. O'Brien, T. O. McDonald, A. Chait, M. D. Allen, and C. E. Alpers Neovascular Expression of E-Selectin, Intercellular Adhesion Molecule-1, and Vascular Cell Adhesion Molecule-1 in Human Atherosclerosis and Their Relation to Intimal Leukocyte Content Circulation, February 15, 1996; 93(4): 672 - 682. [Abstract] [Full Text]

				W. Palinski, R. K. Tangirala, E. Miller, S. G. Young, and J. L. Witztum Increased Autoantibody Titers Against Epitopes of Oxidized LDL in LDL Receptor–Deficient Mice With Increased Atherosclerosis Arterioscler Thromb Vasc Biol, October 1, 1995; 15(10): 1569 - 1576. [Abstract] [Full Text]

				R. K. Tangirala, F. Casanada, E. Miller, J. L. Witztum, D. Steinberg, and W. Palinski Effect of the Antioxidant N,N'-Diphenyl 1,4-Phenylenediamine (DPPD) on Atherosclerosis in ApoE-Deficient Mice Arterioscler Thromb Vasc Biol, October 1, 1995; 15(10): 1625 - 1630. [Abstract] [Full Text]

				M. Y. Chang, M. Sasahara, A. Chait, E. W. Raines, and R. Ross Inhibition of Hypercholesterolemia-Induced Atherosclerosis in the Nonhuman Primate by Probucol : II. Cellular Composition and Proliferation Arterioscler Thromb Vasc Biol, October 1, 1995; 15(10): 1631 - 1640. [Abstract] [Full Text]

				E. Malle, L. Hazell, R. Stocker, W. Sattler, H. Esterbauer, and G. Waeg Immunologic Detection and Measurement of Hypochlorite-Modified LDL With Specific Monoclonal Antibodies Arterioscler Thromb Vasc Biol, July 1, 1995; 15(7): 982 - 989. [Abstract] [Full Text]

				M. O. Pentikainen, K. A. Lindstedt, and P. T. Kovanen Inhibition of the Oxidative Modification of LDL by Nitecapone Arterioscler Thromb Vasc Biol, June 1, 1995; 15(6): 740 - 747. [Abstract] [Full Text]

				K.-i. Hirata, N. Miki, Y. Kuroda, T. Sakoda, S. Kawashima, and M. Yokoyama Low Concentration of Oxidized Low-Density Lipoprotein and Lysophosphatidylcholine Upregulate Constitutive Nitric Oxide Synthase mRNA Expression in Bovine Aortic Endothelial Cells Circ. Res., June 1, 1995; 76(6): 958 - 962. [Abstract] [Full Text]

				W. Palinski, T. Koschinsky, S. W. Butler, E. Miller, H. Vlassara, A. Cerami, and J. L. Witztum Immunological Evidence for the Presence of Advanced Glycosylation End Products in Atherosclerotic Lesions of Euglycemic Rabbits Arterioscler Thromb Vasc Biol, May 1, 1995; 15(5): 571 - 582. [Abstract] [Full Text]

				A. Hammer, G. Kager, G. Dohr, H. Rabl, I. Ghassempur, and G. Jurgens Generation, Characterization, and Histochemical Application of Monoclonal Antibodies Selectively Recognizing Oxidatively Modified ApoB-Containing Serum Lipoproteins Arterioscler Thromb Vasc Biol, May 1, 1995; 15(5): 704 - 713. [Abstract] [Full Text]

				C. Bergmark, R. Wu, U. d. Faire, A. K. Lefvert, and J. Swedenborg Patients With Early-Onset Peripheral Vascular Disease Have Increased Levels of Autoantibodies Against Oxidized LDL Arterioscler Thromb Vasc Biol, April 1, 1995; 15(4): 441 - 445. [Abstract] [Full Text]

				M. J. Stampfer, C. H. Hennekens, J. E. Manson, G. A. Colditz, B. Rosner, and W. C. Willett Vitamin E Consumption and the Risk of Coronary Disease in Women N. Engl. J. Med., May 20, 1993; 328(20): 1444 - 1449. [Abstract] [Full Text]

				S.-F. Yet, R. Tian, M. D. Layne, Z. Y. Wang, K. Maemura, M. Solovyeva, B. Ith, L. G. Melo, L. Zhang, J. S. Ingwall, et al. Cardiac-Specific Expression of Heme Oxygenase-1 Protects Against Ischemia and Reperfusion Injury in Transgenic Mice Circ. Res., July 20, 2001; 89(2): 168 - 173. [Abstract] [Full Text] [PDF]