2.2.2 Oxidized LDL
LDL refers to a class of lipoproteins which main function is to transport cholesterol and triglycerides in the blood for use by various cells. Due to the high blood pressure, plasma constituents continuously seep into the intima of arteries and, at reasonable blood levels LDL particles can pass in and out of the vessel wall. In the blood, LDL particles may be protected from oxidation by blood antioxidants. In excess, LDL tends to get trapped in the matrix, by proteoglycans and other extracellular matrix constituents, where it is subjected to modifications. It has been suggested for more than 20 years that oxidation of lipoproteins is central in the initiation and progression of atherosclerosis, from the early stage conversion of monocytes/macrophages into lipid-laden foam cells and fatty streaks to the late-stage development of coronary artery stenosis, plaque instability, plaque rupture, coronary thrombosis and MI. The oxidative modification hypothesis is based on the concept that LDL in its native form is not atherogenic, and that oxidation of LDL lipids and ApoB-100 is central in the pathogenesis of vascular disease. Whereas native (unmodified) LDL lacks inflammatory properties, modified LDL particles are recognized by the body as foreign, which in turn triggers activation of the immune system and initiation of inflammation.
Figure. Involvement of oxidized LDL in the initiation and progression of the atherosclerotic disease process.
During inflammation a variety of cells (vascular endothelial cells, smooth muscle cells, fibroblasts, neutrophils, monocytes, macrophages) produce inflammatory mediators like oxidants as a defense against disease-causing substances (viruses, bacteria, parasites, tumors, harmful agents). Enzymes like lipoxygenase, cyclooxygenase, phospholipase A2, and myeloperoxidase are believed to be involved in lipid oxidation, resulting in the generation of aldehydes that substitute lysine residues in the ApoB-100 moiety of LDL, and thereby the generation of oxidized LDL (oxLDL). However, lipid peroxidation is not required. Indeed, aldehydes released by endothelial cells under oxidative stress or by activated platelets may also induce the oxidative modification of ApoB-100 in the absence of lipid peroxidation of LDL.
Macrophage scavenger receptors are involved in the removal of oxLDL deposited in the blood vessel wall. The uptake of LDL-cholesterol via the native LDL receptor is subjected to a negative feedback regulation. In contrast, the uptake of oxLDL via scavenger receptors is not down-regulated with increasing intracellular cholesterol content resulting in a massive cholesterol uptake by macrophages, which become foam cells. Foam cells that constitute the fatty streaks in the early stages of atherosclerosis, induce activation of the immune system by the release of inflammatory cytokines.
In the progression of atherosclerosis, an increasing thickening of the intima (plaque formation) is, among other things, due to the intra and extracellular lipid accumulation and the recruitment of monocytes and T-lymphocytes to the artery wall. Smooth muscle cell proliferation and migration to the top of the inflamed intima is stimulated by factors secreted from macrophages, endothelial cells and smooth muscle cells. There they synthesize matrix molecules like collagen, which together with the smooth muscle cells, form a plaque-stabilizing fibrous cap. The fibrous cap may subsequently be degraded by oxLDL-induced secretion of matrix metalloproteinases. If the weakened plaque ruptures, tissue factor, induced during inflammation, will interact with clot-promoting elements in the blood, causing a thrombus to form.
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