Oxidative processes may play an important role in the pathogenesis of many chronic diseases, including atherosclerosis, cancer, arthritis, eye disease, and reperfusion injury during myocardial infarction (MI). Data from in vitro and in vivo studies suggest that oxidative damage to low-density lipoprotein (LDL) promotes several steps in atherogenesis,7 including endothelial cell damage,8,9 foam cell accumulation,1012 and growth13,14 and synthesis of autoantibodies.15 In addition, animal studies suggest that free radicals may directly damage arterial
J.L. Holtzman (ed.), Atherosclerosis and Oxidant Stress: A New Perspective. © Springer 2007
Table 3.1 Natural defense mechanisms against oxidative damage Compartmentalization of oxidative metabolism
Binding of molecular oxygen and reactive species to proteins to prevent random oxidative reactions
Binding of transition metals (e.g., iron and copper) to transport and storage proteins to prevent involvement in free radical reactions Enzymatic antioxidants (e.g., superoxide dismutase, catalase, and glutathione peroxidase) Nonenzymatic antioxidants (e.g., vitamin C, vitamin E, beta-carotene, urate, bilirubin, and ubiquinols)
Mechanisms to repair or dispose of damaged DNA, proteins, lipids, and carbohydrates endothelium,16 promote thrombosis,17 and interfere with normal vasomotor regulation.18 Oxidative damage may enhance atherogenesis by a cascade of reactions.
Several systems have evolved in aerobic organisms to minimize the damaging effects of uncontrolled oxidation (Table 3.1). Mechanisms exist to prevent the formation of unintended free radicals, and oxidative metabolism is carefully compartmentalized with oxygen and its highly reactive species tightly bound to enzymes. Metal ions such as copper and iron are bound to storage or transport proteins to prevent catalytic reactions with oxygen species that could lead to the formation of free radicals. In addition, enzymatic (e.g., superoxide dismutase, catalase, glutathione peroxidase) and nonenzymatic (e.g., vitamins E and C, urate) antioxidants scavenge free radicals, thereby minimizing the damage they can cause once they have been formed. Lastly, there are mechanisms for repairing the damage resulting from unintended oxidative reactions.
Antioxidant vitamins represent one of the many nonenzymatic antioxidant defense mechanisms. Vitamin E (of which alpha-tocopherol is the major component), beta-carotene (a provitamin A), and vitamin C (ascorbic acid) are among the most abundant and most widely studied natural antioxidants. However, there are many other dietary compounds that may function as antioxidants. In vitro data have demonstrated the possible role of these antioxidants in preventing or slowing various steps in atherogenesis by inhibiting the oxidation of LDL or other free radical reactions. These antioxidants have also been shown to prevent experimental atherogenesis in many but not all animal models of atherosclerosis.
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