R. WAYNE ALEXANDER. ATLANTA, GEORGIA ...... spite of having close association with Larry Harker, but there are data showing that on monocytes attached ...
TRANSACTIONS OF THE AMERICAN CLINICAL AND CLIMATOLOGICAL ASSOCIATION, VOL. 109, 1998
ATHEROSCLEROSIS AS A DISEASE OF REDOX-SENSITIVE GENES R. WAYNE ALEXANDER ATLANTA, GEORGIA
OXIDATION AND DISEASE: GENERAL CONSIDERATIONS Over the last decade a tremendous interest has developed in the role of oxidation mechanisms in the pathogenesis of human disease. The accumulating evidence stimulating the increasing investigation in this area has involved primarily the demonstration of the presence of oxidation protein or lipid end-products in multiple disease states, as recently reviewed (1). Based upon the available data, oxidation mechanisms have been posited by Berlett and Stadman (1) to be involved primarily or secondarily in diseases as apparently disparate as Parkinsonism, Alzheimer's and progeria (Table 1 [modified fm ref 1]). These oxidation end-products involve formation of carbonyl groups from the action of free radical intermediates, such as lipid peroxides, or proteins, carbohydrates, or lipids. Examples of these reactions are shown in Figure 1 (1). Oxidatively modified proteins or lipoproteins that have been most prominently implicated in the pathogenesis of cardiovascular disease include oxidized LDL (oxLDL) (2) and advanced glycation end-products (AGEs) (3). Both oxidized LDL and AGEs are TABLE 1 Oxidation Damage and Disease Accumulation Direct Evidence ALS Alzheimer's ARDS
of Oxidized Proteins Muscular Dystrophy Cataracts Rheumatoid Arthritis Parkinson's
Progeria Indirect Evidence Atherosclerosis Diabetes Essential Hypertension
Cystic Fibrosis Ulcerative Colitis
(Modified from ref 1 [Berlett & Stadtman, J Biol Chem,
From the
Department
of Medicine, Division of
Medicine, Atlanta, Georgia. 129
1997]).
Cardiology, Emory University
School of
130
R. WAYNE ALEXANDER
FIG. 1. "Formation of Protein Carbonyls" Modified with permission of authors and J Biol Chem, p. 20315. Formation of protein carbonyls (oxidation end-products) by glycation, glycoxidation and by reactions with peroxidation products of polyunsaturated fatty acids (PUFA). A: reactions of sugars with protein lysyl amino groups (P-NH2). B: michael addition of H-hydroxy-2-nonenal to protein lysine (P-NH2), histidine (P-HIS) or cysteine residues.
biologically active and induce oxidative stress and proinflammatory responses, as discussed subsequently. The important point to note here
is that alteration in the balance between reduction and oxidation (redox) state is emerging as a general theme in the understanding of the pathogenesis of a great variety of diseases. In other words, common disease mechanisms including cell growth, cell death, and elicitation of inflammatory responses are being found, in many instances, to involve alterations in redox state.
ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE An inflammatory component to atherosclerosis has been recognized for at least half a century. Leary in the 1930s and 1940s emphasized the role of the tissue macrophage in forming the foam cell that is a characteristic feature of the atherosclerotic lesion (4). Although the study of atherosclerosis in the early modern era of the 1960s through the 1970s emphasized primarily the role of lipoproteins and their metabolism, a shift in focus to the cell biology of the arterial wall and
REDOX STATE AND ATHEROSCLEROSIS
131
the role of recruited inflammatory cells was in full force by the mid 1980s (5). The presence in human atherosclerotic lesions of T-cells which were activated (6), as well as of macrophages, called attention to the fundamental inflammatory nature of the disease. The evidence was initially summarized by Munro and Cotran (7). The importance of the inflammatory process was emphasized by the subsequent association of plaque rupture in acute myocardial infarction with local accumulation of inflammatory macrophages (8) (Figure 2) and their secretion of metalloproteinases that degrade matrix proteins and compromise the structural integrity of the lesion (9). A central question regarding the pathogenesis of atherosclerosis began to revolve around the issue of defining the mechanisms by which the cells of the arterial wall, primarily the endothelial cells, attract inflammatory mononuclear cells to attach and migrate into the intima.
RECRUITMENT OF INFLAMMATORY CELLS INTO THE ARTERIAL WALL Although adherence of mononuclear cells to the arterial wall has been observed at all stages of atherosclerosis experimentally (10,11) and has been observed consistently in advanced lesions in human autopsy specimens, the approaches to sorting out the mechanisms involved focused on the early stages of the experimental disease. After initiating a high-fat, high-cholesterol diet in rabbits, attachment of mononuclear cells to the endothelium overlying lesion-susceptible areas (areas of low shear stress opposite flow dividers) is observed within several days (10). Using, as reagents, antibodies to adhesion molecules generated from in vitro studies with cytokine-stimulated endothelial cells, Cybulsky et al (12) demonstrated the appearance of putative adhesion proteins at the endothelial surface of cholesterol-fed rabbits concurrently with the attachment of the monocytes (13). These presumptive leukocyte-docking proteins were initially called "atheroELAM" for atherosclerosis-related, Endothelial cell Leukocyte Adhesion Molecule. It was demonstrated subsequently that "athero-ELAM" is the rabbit equivalent of the human adhesion molecule, vascular-cell adhesion molecule-1 (VCAM-1) (13). VCAM-1 is not expressed constituitively in endothelial cells but is inducible. It interacts in a lock-andkey arrangement with its counter ligand, VLA-4, on monocytes and T-cells to contribute to localization and migration of the inflammatory cells into the vascular wall (14) (Figure 3). Although understanding of the molecular mechanisms leading to induction of VCAM-1 and other
132
R. WAYNE ALEXANDER
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