Functions of Vitamin E in Cell Signaling

Both in vitro and in vivo a-tocopherol inhibits platelet aggregation in response to agonists such as arachidonic acid and phorbol ester; the effect seems to be mediated by a protein kinase C mechanism. In cultured cells, a-tocopherol lowers protein kinase C activity, apparently by activating diacylglycerol ki-nase and phosphoprotein phosphatase, and hence initiating the dephospho-rylation and inactivation of protein kinase C (Steiner, 1999; Freedman and Keaney, 2001). Inhibition of protein kinase C is also the mechanism by which a-tocopherol inhibits vascular smooth muscle proliferation, a factor in thrombus formation and platelet aggregation. Neither f-tocopherol nor Trolox has any effect on protein kinase C, platelet aggregation, or vascular smooth muscle proliferation (Azzi et al., 2000, 2001, 2002).

There are a number of actions of a-tocopherol on monocytes and macrophages that suggest it may have a protective role against atherogenesis quite distinct from its antioxidant actions. In monocytes, it reduces formation of reactive oxygen species, cell adhesion to the endothelium, and release of interleukins and tumor necrosis factor. The effect on cell adhesion is from inhibition of protein kinase C. a-Tocopherol inhibits the assembly of the respiratory burst NADPH oxidase that is responsible for oxygen radical generation (Section 7.3.6). The effect on cytokine release is from inhibition of 5-lipoxygenase. In macrophages, it reduces release of interleukin-1 and the activity of the scavenger LDL receptor, thus reducing the accumulation of cholesterol and transformation into foam cells (Jialal et al., 2001; Devaraj et al., 2002).

a-Tocopherol modulates transcription of a number of genes. It induces the liver a-tocopherol transfer protein and a-tropomyosin in smooth muscle, whereas it represses the age-related increase in synthesis of collagenase

(metalloproteinase 1) in fibroblasts in culture, and the expression of the scavenger receptors for oxidized LDL in macrophages and smooth muscle. With the exception of the induction of a-tocopherol transfer protein, in which ยก-tocopherol is also active, these responses are specific for a-tocopherol. It is likely that these transcriptional actions are mediated by binding to the a-tocopherol-associated protein, a hydrophobic-ligand protein that specifically binds a-tocopherol and is expressed in all tissues; however, as yet, no response element for this protein has been identified on any of the proposed target genes (Azzi et al., 2000, 2001, 2002).

In experimental animals, vitamin E deficiency depresses immune system function, with reduced mitogenesis of B and T lymphocytes, reduced phagocytosis and chemotaxis, and reduced production of antibodies and interleukin-2. This suggests a signaling role in the immune system (Moriguchi and Muraga, 2000).

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