The hypothesis that oxidative stress plays an important role in the pathogenesis of atherosclerosis is generally accepted. Substantial in vitro evidence indicates that oxidized LDL is the component central to the initiation and/or progression of athero-genesis at the molecular and cellular level. The typical LDL particle is not only rich in cholesterol but also contains approximately 1300 molecules of RH, which are very sensitive to oxidation. Vitamin E, mainly a-tocopherol, is quantitatively the most important lipophilic antioxidant present in LDL particles. On average, each LDL particle is protected by ~6mol a-tocopherol (range, 3-15 mol), 1 mol of 7-tocopherol, and small amounts of carotenoids.
All major cells of the artery wall, such as mono-cyte macrophages, endothelial cells, and smooth muscle cells, can modify LDL oxidatively in vitro. Monocytes have been shown to induce peroxidation of lipids such as those in LDL by the generation of reactive species, including superoxide anion, hydrogen peroxide, and hydroxyl radicals. Other oxidants have been implicated, including 15-lipoxygenase, myeloperoxidase-generated hypochlorous acid, and reactive nitrogen species such as peroxynitrite. In vivo, oxidized LDL particles are recognized by macrophage scavenger receptors and taken up by macrophages, forming lipid-laden foam cells in the fatty streak lesions. The free radical oxidation of LDL results in numerous structural changes that all depend on a common event—the peroxidation of polyunsaturated fatty acids in the LDL particle.
In vitro studies have indicated that increasing the vitamin E content of LDL particles increases their resistance to oxidation and decreases their uptake by macrophages. Vitamin E supplementation has also been reported to suppress macrophage uptake of oxidized LDL in human arterial lesions and decrease urinary F2-isoprostane (a 'footprint' of free radical-mediated oxidation of arachidonic acid) concentrations. Reactive nitrogen species are also implicated in aortic oxidation of LDL and therefore potentially in atherosclerosis. Because of the nonsubstituted 5-position, 7-tocopherol reacts with peroxynitrite and other electrophilic mutagens generated during inflammation and forms a stable carbon-centered adduct, 5-nitro-7-tocopherol. This mechanism of protecting LDL may be significant when 7-tocopherol constitutes a major portion of vitamin E in the diet. It is worth noting that the ability of 7-tocopherol to attenuate oxidative damage produced by these reactive species may prevent or delay the progression of other diseases as well as cardiovascular disease
(CVD), in which inflammation plays a role, such as cancer, rheumatoid arthritis, inflammatory bowel disease, and neurodegenative disorders. In addition, 7-CEHC has natriuretic activity and functions in the kidney to control sodium excretion, and it regulates the body's extracellular fluid volume, an important determinant in hypertension and congestive heart failure.
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