Mechanisms of LDL Oxidation

Oxidative stress is generally thought to play an important contributory role in the pathogenesis of atherosclerosis. Although there are many determinants in the development of this disease, substantial in vitro evidence links the production of oxidized forms of LDL to molecular processes involved in atherogenesis (1–7). Depending on how LDL oxidation is initiated and the level of damage produced, a spectrum of damaged particles and biological effects are observed. Thus, LDL possessing low levels of oxidative damage induces the expression of chemoattractants and adhesion molecules, thereby facilitating tethering, activation and attachment of monocytes to endothelial cells (8–12). In addition, low level oxidative damage to LDL results in the formation of oxidized lipids that can impair the function of key elements of the anti-atherogenic reverse cholesterol transport pathway (13). More pronounced oxidative damage to LDL increases its atherogenicity by inhibiting endothelium-derived relaxing factor (14,15) and exerting cytotoxic effects (16,17). Moreover, oxidized LDL can induce foam cell formation, since after sufficient oxidative modification LDL is taken up by the poorly-regulated scavenger receptor pathway bypassing the cells normal cholesterol homeostatic mechanisms (18,19).