2.2.7. Atherogeneity of oxidized LDL
In the early stages, uptake of Ox-LDL by macrophage may be protective. When too much Ox-LDL accumulates in macrophage, irreversible damage occurs, resulting in foam cell formation, cell death, and release of many modified molecules with diverse effects (Witztum et al. 1991, Witztum 1994). As a result of accumulation of lipid deposits in foam cells, the arterial wall evolves from the initial fatty streak to form the lipid-rich atheromatous core and an overlying dense fibrocellular layer, comprising primarily of SMCss.
Ox-LDL is the prerequisite for macrophage uptake and cellular cholesterol accumulation (Steinberg et al. 1989). Therefore, it has potential atherogenic properties in the initiation and development of the atherosclerotic lesion (Ross 1993, Steinberg 1997b).
In addition to the foam cell formation, Ox-LDL can also play other roles. It promotes atherosclerosis by recruitment and retention of monocytes and T cells in the intima, migration of SMC from media into intima where these cells will become foam cell-like after having taken up Ox-LDL, by its cytotoxicity toward EC and by stimulating monocyte adhesion to the endothelium. In addition, the Ox-LDL or its products may induce cellular expression of potent chemotactic factors, such as monocyte chemotactic protein 1, and secretion of colony-stimulating factors, such as macrophage colony-stimulating factor, which can stimulate SMC proliferation and differentiation of monocytes into macrophages.
Ox-LDL is also immunogenic with antibodies to epitopes of Ox-LDL found in plasma and in lesions associated with immune complexes. In addition, CD4+ T cells have been isolated from human atherosclerotic plaques and up to 10% of these clones proliferate and release cytokines on exposure to Ox-LDL. This response is dependent on autologous antigen-presenting cells and restricted by HLA-DR. Thus there is both a humoral and a cell-mediated immune response, typical of an inflammatory lesion (Witztum 1994).
Ox-LDL enhances platelet adhesion and aggregation, which may stimulate macrophage foam cell formation and SMC proliferation.
Ox-LDL may alter other vital properties of the arterial wall with clinical or fatal consequences such as impairing vasodilation (Holvoet and Collen 1998).
Ox-LDL can induce vascular cell apoptosis which is involved in atherosclerosis formation (Nishio et al. 1996, Li et al. 1998).
Ox-LDL, or its products, can profoundly impair the nitric-oxide-mediated vasorelaxation of coronary arteries in response to agents such as acetylcholine.
Hypercholesterolaemia, by generation of more Ox-LDL in the intima or by creation of a prooxidant environment that stimulates EC to release more superoxide anion, may contribute importantly to vasospasm even in the absence of significant lesions.
Certain products of Ox-LDL, such as oxysterols, are highly toxic to EC and could initiate breaks in endothelial integrity.
Other products may stimulate tissue-factor release and initiate coagulation and thrombosis.
Because the shoulder regions of even established lesions are rich in macrophage-filled foam cells containing Ox-LDL (it is at these sites that plaque rupture and thrombotic events occur), Ox-LDL probably participates in this late stage as well.
Thus, Ox-LDL may contribute to atherogenesis and CHD by mechanisms other than macrophage foam-cell formation alone.
The pathological process of Ox-LDL initiated atherosclerotic lesion formation is shown in Fig. 4. Accordingly, the intervention and prevention of Ox-LDL should be the primary goal of therapy.
Figure 4. Pathway for Ox-LDL initiated atherosclerotic lesion formation.
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