MODULATION OF ACTIVATOR PROTEIN-1 (AP-1) TRANSCRIPTION FACTOR AND PROTEIN-KINASE-C BY HYDROGEN-PEROXIDE AND D-ALPHA-TOCOPHEROL IN VASCULAR SMOOTH-MUSCLE CELLS

The effects of hydrogen peroxide, D-alpha-tocopherol and of D-beta-toc opherol on proliferation, protein kinase C and activator protein-1 (AP -1) activation have been studied in vascular smooth muscle cells. Cell proliferation, when activated by foetal calf serum, was inhibited by D-alpha-tocopherol. Protein kinase C activity was stimulated by hydrog en peroxide in a manner similar to phorbol myristate acetate; in the l atter case, but not in the former, D-alpha-tocopherol inhibited the re action. Hydrogen peroxide prevented phorbol-myristate-acetate-stimulat ed AP-1 binding to DNA but stimulated it if protein kinase C was down- regulated or inhibited. D-alpha-Tocopherol promoted AP-1 activation in quiescent cells but prevented its activation by phorbol myristate ace tate. None of the described effects of D-alpha-tocopherol were shared by D-beta-tocopherol, suggesting a non-antioxidant mechanism as the ba sis of its action. The data show that hydrogen peroxide and D-alpha-to copherol affect more than one element in the cell signal-transduction cascade.