Oxidative Stress

The "oxidative modification of lipoproteins" hypothesis of atherosclerosis proposes that LDL oxidation plays a pivotal role in early atherogenesis.82-92 This hypothesis is supported by evidence that LDL oxidation indeed occurs in vivo93 and contributes to the clinical manifestation of atherosclerosis. The uptake of Ox-LDL via scavenger receptors promotes cholesterol accumulation and foam cell formation,94,95 the hallmark of early atherosclerosis. In addition, Ox-LDL atherogenicity is related to recruitment of monocytes to the intima,96 stimulation of monocyte adhesion to the endothelium,97 and its cytotoxicity toward arterial cells.98,99 The process of LDL oxidation appears to occur within the artery wall, and all major cells of the artery wall, including endothelial cells, smooth muscle cells and monocyte-derived macrophages can oxidize LDL.100,101 Macrophage-mediated oxidation of LDL is a key event during early atherogenesis102 and requires the binding of LDL to the macrophage LDL receptor.103 The interaction of LDL with macrophages under oxidative stress activates cellular oxygenases, which can then produce ROS capable of oxidizing LDL.104,105 Under oxidative stress, not only are LDL and the other plasma lipoproteins oxidized, but cell lipid peroxidation takes place, including arterial mac-rophages.106 Such "oxidized macrophages" can easily oxidize LDL.107 The oxidation rate of LDL was shown to be reduced by dietary antioxidant intervention.108 The oxidative hypothesis of atherosclerosis has stimulated extensive investigation on the role of antioxidants as a possible preventive treatment for atherosclerosis. Macrophage foam cell formation during early atherogenesis is determined by the balance between pro-oxidants and antioxidants in arterial wall cells, as well as in plasma lipoproteins.109 Epidemiological studies have demonstrated an association between increased intake of antioxidant vitamins and reduced morbidity and mortality from coronary artery disease (CAD).110,111 The beneficial health effects attributed to the consumption of fruits and vegetables are related, at least in part, to their antioxidant activity.112-115 Some antioxidants that prevent oxidative stress were shown to protect LDL from oxidation, and in parallel, to reduce the development of the atherosclerotic lesions.116,117

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