RRR-ALPHA-TOCOPHEROL REGULATION OF GENE-TRANSCRIPTION IN RESPONSE TO THE CELL OXIDANT STATUS

RRR-alpha-Tocopherol, but not RRR-beta-tocopherol, negative regulates proliferation of vascular smooth muscle cells at physiological concent rations. At the same concentrations RRR-alpha-tocopherol inhibits prot ein kinase C activity, whereas RRR-beta-tocopherol is ineffective. Fur thermore, RRR-beta-tocopherol prevents the inhibition of cell growth a nd of protein kinase C activity caused by RRR-alpha-tocopherol. The ne gative regulation by RRR-alpha-tocopherol of protein kinase C activity appears to be the cause of smooth muscle cell growth inhibition. RRR- alpha-Tocopherol does not act by binding to protein kinase C directly but presumably by preventing protein kinase C activation. A second RRR -alpha-tocopherol effect has been found at the level of AP 1, the latt er becoming activated by RRR-alpha tocopherol under condition of prote in kinase C inhibition or down regulation. AP-1 inhibition by RRR-alph a-tocopherol is seen, however, under condition of protein kinase C sti mulation. Compositional changes of AP-1 have been found to be at the b asis of the RRR-alpha-tocopherol effects. RRR-beta-Tocopherol, provide d with similar antioxidant properties, not only it does not affect AP 1 but it prevents the effects of RRR-alpha-tocopherol. Moreover, it ha s been observed that RRR-alpha-tocopherol is able to affect TRE regula ted gene transcription. It concluded that RRR-alpha-tocopherol acts sp ecifically in vascular smooth muscle cells, by controlling a signal tr ansduction pathway leading to cell proliferation by a non-antioxidant mechanism.