The Oxidized LDL Hypothesis

Low density lipoproteins (LDL) are plasma particles that contain in association with protein several types of lip-ids with a predominance of phospholipids, free and es-terified cholesterol, for a total of about 1200 unsaturated fatty acid chains. In the presence of high levels of LDL - a well-recognized risk factor for developing atherosclerosis - influx of cholesterol and LDL into the intima is increased. In addition to binding to connective tissue elements (such as proteoglycans), accumulated LDL is progressively oxidized [36-38, 56] (Fig. 1.2.4). This increased oxidation gives rise to the production of several toxic products. For example, free radicals chain reaction within the lipid chains form hydroperoxides that easily break down, generating aldehydes (malonaldehyde, 4-hy-droxynonenal) and other toxic substances that can react with lysine moieties in the B-apoprotein part of the LDLs. Other toxic products include for example 7-^-hydroper-oxycholesterol, 7-ketocholesterol, lysophosphatidylcho-line, oxidized fatty acid and epoxy sterols [18].

Native (nonoxidized) LDLs are collected by the extremely specific LDL receptors, and then cleared by a nonatherogenous process. In contrast, the oxidatively modified LDLs are not recognized by these receptors. They are metabolized in an unregulated way by scavenger receptors expressed by the macrophages present in the vascular wall and derived from the circulating mono-cytes, as mentioned previously [48]. Removal and sequestration of modified LDLs by macrophages may be considered a protective role minimizing the effects of modified

Modified Ldl

Fig. 1.2.4 Role of LDL oxidation in atheromatous plaque formation. After oxidation, LDLs exert toxic effects on endothelial cells with resultant expression of cell adhesion molecules and release of growth factors. Oxidized LDL also stimulates smooth muscle cell proliferation. After endocytosis of oxidized LDL, macrophages transform into foam cells. (E-selectin Endothelial selectin, GM-CSF granulocyte-monocyte-colony stimulating factor, ICAM-1 intercellular adhesion molecule-1, LDL low density lipoprotein, Lyso-PC lysophosphatidylcholine, MCP-1 monocyte chemoattractant protein-1, ox-chol oxidized cholesterol VCAM-1 vascular cell adhesion molecule)

Fig. 1.2.4 Role of LDL oxidation in atheromatous plaque formation. After oxidation, LDLs exert toxic effects on endothelial cells with resultant expression of cell adhesion molecules and release of growth factors. Oxidized LDL also stimulates smooth muscle cell proliferation. After endocytosis of oxidized LDL, macrophages transform into foam cells. (E-selectin Endothelial selectin, GM-CSF granulocyte-monocyte-colony stimulating factor, ICAM-1 intercellular adhesion molecule-1, LDL low density lipoprotein, Lyso-PC lysophosphatidylcholine, MCP-1 monocyte chemoattractant protein-1, ox-chol oxidized cholesterol VCAM-1 vascular cell adhesion molecule)

LDL. Nevertheless, this route is atherogenous, since the internalization of LDL by macrophages leads to the formation of lipid peroxides and facilitates the transformation of macrophages into foam cells [60]. Vitamins C and E protect LDLs against oxidation and protective effects of vitamin E supplementation have been suggested in some reports [17].

In addition to their ability to injure macrophages, oxidized LDLs contribute to the perpetuation of the inflammatory reaction and to progression of the plaque, mainly for two reasons [35]. First, oxidized LDLs are implicated in the recruitment and proliferation of monocytes and lymphocytes, notably via upregulation of gene expression for MCP-1 and for M-CSF. This inflammatory response increases the inward movement of lipoprotein within the artery, leading to a positive feedback. This induces a vicious cycle favouring development and progression of the plaque. Second, autoantibodies directed toward modified LDLs are produced. Along with scavenging of LDL, immune complexes taken up by macrophages stimulate the release of cytokines and growth factors by macrophages, thus contributing to stimulation of SMC migration and proliferation.

Diabetes is often associated with an accelerated course and a diffuse character of atherosclerosis, especially in peripheral arteries, with devastating cardiovascular complications. In this case, the nonenzymatic glycosylation process of LDL impairs binding of LDL to its receptor and increases the formation of foam cells [22]. This process is facilitated since vascular permeability is increased subsequent to alteration of the components of the extracellular matrix and to thickening of the basement membrane [54].

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