(Circulation. 1995;91:2488-2496.)
© 1995 American Heart Association, Inc.
Articles |
Atherosclerosis: Basic Mechanisms
Oxidation, Inflammation, and Genetics
From the Atherosclerosis Research Unit and the Departments of Medicine (J.A.B., M.N., A.M.F., J.S.F., L.L.D., P.A.E., A.J.L.), Pathology (J.A.B., A.D.W.), Physiology (J.S.F., L.L.D.), Biological Chemistry (P.A.E.), and Microbiology and Molecular Genetics (A.J.L.), University of California School of Medicine, Los Angeles, and the College of Letters and Sciences (A.J.L.), Los Angeles, Calif.
Correspondence to Alan M. Fogelman, MD, Department of Medicine, UCLA School of Medicine, Los Angeles, CA 90024-1736.
Abstract The clinical events resulting from atherosclerosis
are directly related to the oxidation of lipids in LDLs that become
trapped in the extracellular matrix of the subendothelial space. These
oxidized lipids activate an NF
B-like transcription factor and induce
the expression of genes containing NFB binding sites. The protein
products of these genes initiate an inflammatory response that
initially leads to the development of the fatty streak. The progression
of the lesion is associated with the activation of genes that induce
arterial calcification, which changes the mechanical characteristics of
the artery wall and predisposes to plaque rupture at sites of monocytic
infiltration. Plaque rupture exposes the flowing blood to tissue factor
in the lesion, and this induces thrombosis, which is the proximate
cause of the clinical event. There appear to be potent genetically
determined systems for preventing lipid oxidation, inactivating
biologically important oxidized lipids, and/or modulating the
inflammatory response to oxidized lipids that may explain the differing
susceptibility of individuals and populations to the development of
atherosclerosis. Enzymes associated with HDL may play an important role
in protecting against lipid oxidation in the artery wall and may
account in part for the inverse relation between HDL and risk
for atherosclerotic clinical events.
Key Words: atherosclerosis • lipids • genes • antioxidants • lipoproteins
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G. N. Fredrikson, B. Hedblad, G. Berglund, R. Alm, M. Ares, B. Cercek, K.-Y. Chyu, P. K. Shah, and J. Nilsson Identification of Immune Responses Against Aldehyde-Modified Peptide Sequences in ApoB Associated With Cardiovascular Disease Arterioscler Thromb Vasc Biol, May 1, 2003; 23(5): 872 - 878. [Abstract] [Full Text] [PDF]
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A. E. May, V. Redecke, S. Gruner, R. Schmidt, S. Massberg, T. Miethke, B. Ryba, C. Prazeres da Costa, A. Schomig, and F.-J. Neumann Recruitment of Chlamydia pneumoniae-Infected Macrophages to the Carotid Artery Wall in Noninfected, Nonatherosclerotic Mice Arterioscler Thromb Vasc Biol, May 1, 2003; 23(5): 789 - 794. [Abstract] [Full Text] [PDF]
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H. Kirii, T. Niwa, Y. Yamada, H. Wada, K. Saito, Y. Iwakura, M. Asano, H. Moriwaki, and M. Seishima Lack of Interleukin-1{beta} Decreases the Severity of Atherosclerosis in ApoE-Deficient Mice Arterioscler Thromb Vasc Biol, April 1, 2003; 23(4): 656 - 660. [Abstract] [Full Text] [PDF]
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M. Schoppet, A. M. Sattler, J. R. Schaefer, M. Herzum, B. Maisch, and L. C. Hofbauer Increased Osteoprotegerin Serum Levels in Men with Coronary Artery Disease J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1024 - 1028. [Abstract] [Full Text] [PDF]
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J. D. Morrow Is Oxidant Stress a Connection Between Obesity and Atherosclerosis? Arterioscler Thromb Vasc Biol, March 1, 2003; 23(3): 368 - 370. [Full Text] [PDF]
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 U. Landmesser and H. Drexler Oxidative stress, the renin-angiotensin system, and atherosclerosis Eur. Heart J. Suppl., January 1, 2003; 5(suppl_A): A3 - A7. [Abstract] [PDF]
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R. De Caterina and C. Manes Inflammation in early atherogenesis: impact of ACE inhibition Eur. Heart J. Suppl., January 1, 2003; 5(suppl_A): A15 - A24. [Abstract] [PDF]
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C. R. Kiefer, J. B. McKenney, J. F. Trainor, and L. M. Snyder Maturation-Dependent Acquired Coronary Structural Alterations and Atherogenesis in the Dahl Sodium-Sensitive Hypertensive Rat Circulation, November 5, 2002; 106(19): 2486 - 2490. [Abstract] [Full Text] [PDF]
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K. Nishi, H. Itabe, M. Uno, K. T. Kitazato, H. Horiguchi, K. Shinno, and S. Nagahiro Oxidized LDL in Carotid Plaques and Plasma Associates With Plaque Instability Arterioscler Thromb Vasc Biol, October 1, 2002; 22(10): 1649 - 1654. [Abstract] [Full Text] [PDF]
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H. Kaneda, M. Ohno, J. Taguchi, M. Togo, H. Hashimoto, K. Ogasawara, T. Aizawa, N. Ishizaka, and R. Nagai Heme Oxygenase-1 Gene Promoter Polymorphism Is Associated With Coronary Artery Disease in Japanese Patients With Coronary Risk Factors Arterioscler Thromb Vasc Biol, October 1, 2002; 22(10): 1680 - 1685. [Abstract] [Full Text] [PDF]
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V. Raos and B. J. Strujic Dyslipoproteinemia and Coronary Disease Angiology, September 1, 2002; 53(5): 557 - 562. [Abstract] [PDF]
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 I. Bureau, F. Laporte, M. Favier, H. Faure, M. Fields, A. E. Favier, and A.-M. Roussel No Antioxidant Effect of Combined HRT on LDL Oxidizability and Oxidative Stress Biomarkers in Treated Post-Menopausal Women J. Am. Coll. Nutr., August 1, 2002; 21(4): 333 - 338. [Abstract] [Full Text] [PDF]
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T. C. Major, L. Liang, X. Lu, W. Rosebury, and T. M.A. Bocan Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) Is Induced Upon Monocyte Differentiation and Is Expressed in Human Atheroma Arterioscler Thromb Vasc Biol, July 1, 2002; 22(7): 1200 - 1207. [Abstract] [Full Text] [PDF]
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L. J. Pinderski, M. P. Fischbein, G. Subbanagounder, M. C. Fishbein, N. Kubo, H. Cheroutre, L. K. Curtiss, J. A. Berliner, and W. A. Boisvert Overexpression of Interleukin-10 by Activated T Lymphocytes Inhibits Atherosclerosis in LDL Receptor-Deficient Mice by Altering Lymphocyte and Macrophage Phenotypes Circ. Res., May 31, 2002; 90(10): 1064 - 1071. [Abstract] [Full Text] [PDF]
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J. L. Sanchez-Quesada, S. Benitez, C. Otal, M. Franco, F. Blanco-Vaca, and J. Ordonez-Llanos Density distribution of electronegative LDL in normolipemic and hyperlipemic subjects J. Lipid Res., May 1, 2002; 43(5): 699 - 705. [Abstract] [Full Text] [PDF]
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E. Boisfer, D. Stengel, D. Pastier, P. M. Laplaud, N. Dousset, E. Ninio, and A.-D. Kalopissis Antioxidant properties of HDL in transgenic mice overexpressing human apolipoprotein A-II J. Lipid Res., May 1, 2002; 43(5): 732 - 741. [Abstract] [Full Text] [PDF]
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 B. A. Wasserman, W. I. Smith, H. H. Trout III, R. O. Cannon III, R. S. Balaban, and A. E. Arai Carotid Artery Atherosclerosis: In Vivo Morphologic Characterization with Gadolinium-enhanced Double-oblique MR Imaging—Initial Results Radiology, May 1, 2002; 223(2): 566 - 573. [Abstract] [Full Text] [PDF]
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 T. E. Akiyama, S. Sakai, G. Lambert, C. J. Nicol, K. Matsusue, S. Pimprale, Y.-H. Lee, M. Ricote, C. K. Glass, H. B. Brewer Jr., et al. Conditional Disruption of the Peroxisome Proliferator-Activated Receptor {gamma} Gene in Mice Results in Lowered Expression of ABCA1, ABCG1, and apoE in Macrophages and Reduced Cholesterol Efflux Mol. Cell. Biol., April 15, 2002; 22(8): 2607 - 2619. [Abstract] [Full Text] [PDF]
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F. Basso, G. D.O. Lowe, A. Rumley, A. D. McMahon, and S. E. Humphries Interleukin-6 -174G>C Polymorphism and Risk of Coronary Heart Disease in West of Scotland Coronary Prevention Study (WOSCOPS) Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 599 - 604. [Abstract] [Full Text] [PDF]
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W. Shi, X. Wang, K. Tangchitpiyanond, J. Wong, Y. Shi, and A. J. Lusis Atherosclerosis in C3H/HeJ Mice Reconstituted With Apolipoprotein E-Null Bone Marrow Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 650 - 655. [Abstract] [Full Text] [PDF]
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A. Hockerstedt, M. J. Tikkanen, and M. Jauhiainen LCAT facilitates transacylation of 17{beta}-estradiol in the presence of HDL3 subfraction J. Lipid Res., March 1, 2002; 43(3): 392 - 397. [Abstract] [Full Text] [PDF]
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G.F. Gensini and B. Dilaghi The unstable plaque Eur. Heart J. Suppl., March 1, 2002; 4(suppl_B): B22 - B27. [Abstract] [PDF]
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G. Subbanagounder, J. W. Wong, H. Lee, K. F. Faull, E. Miller, J. L. Witztum, and J. A. Berliner Epoxyisoprostane and Epoxycyclopentenone Phospholipids Regulate Monocyte Chemotactic Protein-1 and Interleukin-8 Synthesis. FORMATION OF THESE OXIDIZED PHOSPHOLIPIDS IN RESPONSE TO INTERLEUKIN-1beta J. Biol. Chem., February 22, 2002; 277(9): 7271 - 7281. [Abstract] [Full Text] [PDF]
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G. Arcaro, A. Cretti, S. Balzano, A. Lechi, M. Muggeo, E. Bonora, and R. C. Bonadonna Insulin Causes Endothelial Dysfunction in Humans: Sites and Mechanisms Circulation, February 5, 2002; 105(5): 576 - 582. [Abstract] [Full Text] [PDF]
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Y. Tintut, J. Patel, M. Territo, T. Saini, F. Parhami, and L. L. Demer Monocyte/Macrophage Regulation of Vascular Calcification In Vitro Circulation, February 5, 2002; 105(5): 650 - 655. [Abstract] [Full Text] [PDF]
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Z.-B. Lei, Z. Zhang, Q. Jing, Y.-W. Qin, G. Pei, B.-Z. Cao, and X.-Y. Li OxLDL upregulates CXCR2 expression in monocytes via scavenger receptors and activation of p38 mitogen-activated protein kinase Cardiovasc Res, February 1, 2002; 53(2): 524 - 532. [Abstract] [Full Text] [PDF]
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H. Kamido, H. Eguchi, H. Ikeda, T. Imaizumi, K. Yamana, K. Hartvigsen, A. Ravandi, and A. Kuksis Core aldehydes of alkyl glycerophosphocholines in atheroma induce platelet aggregation and inhibit endothelium-dependent arterial relaxation J. Lipid Res., January 1, 2002; 43(1): 158 - 166. [Abstract] [Full Text] [PDF]
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M. Toborek, Y. W. Lee, R. Garrido, S. Kaiser, and B. Hennig Unsaturated fatty acids selectively induce an inflammatory environment in human endothelial cells Am. J. Clinical Nutrition, January 1, 2002; 75(1): 119 - 125. [Abstract] [Full Text] [PDF]
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