Oxidized Low-density Lipoproteins: What Is Understood and What Remains to Be Clarified.

Abstract

Oxidized low-density lipoprotein (OxLDL) has previously been thought to promote atherogenesis through foam cell formation. However, the actual nature of OxLDL present in vivo remained obscure until recently. We have produced a monoclonal antibody, DLH3, which specifically binds to OxLDL but not to native LDL. The presence of OxLDL in the LDL fraction of human plasma was demonstrated by introducing a sandwich ELISA procedure using DLH3 together with an anti-apoB antibody. Furthermore, OxLDL levels appeared to increase in certain pathological conditions including acute myocardial infarction and carotid artery atherosclerosis. Accumulation of OxLDL in atherosclerotic lesions has also been demonstrated by immunohistochemical and biochemical studies using the DLH3 antibody. This antibody recognizes oxidized phosphatidylcholines (OxPC) generated during oxidative modification of LDL, and OxPC-apoB adducts formed in OxLDL are the presumed antigens. Measuring OxLDL in plasma would be a useful diagnostic tool for cardiovascular diseases. However, there still remain some major questions related to OxLDL, the answers to which are crucial for understanding the mechanisms of atherogenesis.Key word atherosclerosis; oxidized low-density lipoprotein (LDL); foam cell; oxidized phosphatidylcholine; macrophage contact. A mesh-shaped sheet of elastin called elastic lamina lies between the endothelial cells and the layers of smooth muscle cells. There is accumulation of collagen fibers and lipids, and invasion of various cells including macrophages between the endothelial cells and the elastic lamina in the earliest stages of atherosclerotic lesions, which is referred as to as diffuse intimal thickening (Fig. 1b). Fatty streaks are macroscopic lumps on the vessel walls which coalesce to form long lesions. In this stage, there is massive acculumation of lipids in intimal areas and large numbers of macrophage-derived foam cells are found. Some foam cells are generated from smooth muscle cells (Fig. 1c). Fibrous caps are formed with smooth muscle cells and numerous fibrous proteins such as collagens are found in atheromata. In the deep regions of the atheroma, massive accumulations of macrophages, smooth muscle cells and extracellular matrix proteins are found (Fig. 1d).When the luminal surface of the atherosclerotic lesion is damaged or cracked, platelets immediately adhere and aggregate at the cracked sites and subsequently generate thrombi (Fig. 1e). Thrombus formation can lead to complete occlusion of the blood vessel, and is the primary cause of myocardial and cerebral infarction. From a number of research findings it has been presumed that atheromatous lesions enriched with lipids or foam cells become vulnerable and prone to rupture.Russel Ross proposed the so-called "modified injury-response hypothesis" as a possible mechanism of development of atheroslcerosis.22) When endothelial cells are injured or stressed, they respond to the injury by inducing various cytokines. Then, the cytokines activate other types of cells such as macr...

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Antioxidant Effects of Statins in the Management of Cardiometabolic Disorders

“…In addition, several studies have demonstrated the antioxidative properties of statins 6,11) , andithaspreviouslybeenshown,bothinvitroandin vivo, that statins inhibit lipid and lipoprotein oxidation, thereby suppressing ROS formation and/or bluntingthedamagingeffectsoftheseradicals 6,12) . The oxidative modification of LDL particles in thevesselwallplaysacriticalroleinthedevelopment of atherosclerosis 13,14) . Therefore, reducing oxidized LDL is a potentially effective method for mitigating the atherogenicity of LDL particles.…”

“…Several in vitro studies have shown that lipid-laden foam cells are formed after macrophages take up oxidized LDL 10,28,29) . In addition, the presence of lipid-laden foam cells is a typical feature of vulnerable atherosclerotic lesions.Therefore, the oxidativemodificationofLDLplaysaroleinthedevelopmentofatheroscleroticlesionsviatheformationof foamcells 13) .Recentevidenceindicatesthatmodified apolipoproteinBderivedfromoxidizedLDLaccumulates in foam cells 29) . Furthermore, macrophagederivedfoamcellscontainmanylipiddropletsinthe cytoplasm, and the levels of oxidized LDL are increased in patients with a history of acute myocardialinfarctionandcarotidarteryatherosclerosis 28,[30][31][32] .…”