Tocopherols and Other Metabolic Functions

Vitamin E, in addition to having a protective role in the oxidative modification of LDL, may affect or limit the progression of atherosclerosis and a number of other conditions in ways that are unrelated to its antioxidant activity. Some of these effects appear to stem from the ability of a-tocopherol, at physiological concentrations of vitamin E, to activate protein phosphatase 2A, which inhibits the activity of protein kinase C (PKC), a biological indicator of inflammation, by dephosphorylating the protein. PKC is an important element in the signal transduc-tion cascade mediated by growth factors, such as platelet-derived growth factors, which are necessary for the progression and completion of the cell proliferation cycle.

The cellular effects of a-tocopherol-mediated inhibition of PKC depend on the cell type in question, but the cumulative effect is highly protective against the progression of atherosclerosis. PKC inhibition results in reduced smooth muscle cell proliferation, inhibition of platelet aggregation, and thus delayed intra-arterial thrombus formation. Endothelial cell function is preserved by the downregulation of adhesion molecule (ICAM-1 and VCAM-1) expression (possibly by downregulation of nuclear factor-^B) and hence prevention of monocyte and neutrophil adhesion, which is an important early event in the initiation of fatty streak formation and atherogenesis. In addition, PKC inhibition in monocytes reduces the production of reactive oxygen species by impairment of NADPH-oxidase assembly, which may help to reduce LDL oxidation.

The release of proinflammatory cytokines in monocytes, such as interleukin-1^ and tumour necrosis factor-a, is impeded by a-tocopherol-mediated inhibition of the 5-lipoxygenase pathway, and production of eicosanoids, such as prostaglan-din E2 and thromboxane A2, is impeded by 7-tocopherol-mediated inhibition of the cycloxygen-ase pathway. Lower circulating levels of inflammatory mediators, which are aggregatory and vasoconstrictive, as well as inhibition of monocyte chemoattractant protein-1 (MCP-1) production, reduces the attraction of monocytes to inflammatory sites at the arterial wall and prevents the formation of foam cells. Furthermore, a-tocopherol increases production of prostacyclin, which has anti-aggrega-tory and vasodilatory properties, thereby reducing the risk of a coronary event. There is evidence that in a formed atherosclerotic plaque, vitamin E may have a stabilizing effect and prevent its rupture and subsequent clot formation. This may be an important contributor to the prevention of heart disease because plaque types that are most subject to rupture present the greatest threat.

Nitric oxide (NO) produced by NO synthase in the endothelium is important in the maintenance of vascular tone; it suppresses the expression of proin-flammatory cytokines, adhesion molecules, and MCP-1. It also inhibits platelet adhesion, maintains the integrity of the arterial wall, and acts as an antioxidant. Vitamin E can reduce the inhibition of NO synthase by reactive oxygen species, thus maintaining NO production, either through its antioxi-dant activity or perhaps by suppressing PKC activity in smooth muscle.

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