Modulation by Oxidants and Antioxidants of Signal Transduction and Smooth Muscle Cell Proliferation

Arteriosclerosis, restenosis, and hypertension as well as a number of other vascular diseases are characterized by vascular smooth muscle cell proliferation.1-4 Smooth muscle cell growth is regulated by specific factors released from blood cells,1-5 by the vessel wall cells3,6 and by natural compounds, such as tocopherols. Active oxygen species (i.e., O2, H2O2, and OH) may act as vascular smooth muscle growth factors by inducing proto-oncogene expression and DNA synthesis,7,8 and antioxidants can retard atherosclerosis and foam cell formation as shown in animal model,9,10 and human studies.11-14 Tocopherols, well-established natural antioxidants, may in some cases stimulate cell proliferation by preventing the formation of growth-inhibitory lipid peroxides.15-19 In addition to having antioxidant properties, RRR-α-tocopherol is a cell growth inhibitor, this effect being unrelated with its radical scavenger properties.20,21 Parallel to the inhibition of cell proliferation, RRR-α-tocopherol has been shown to inhibit protein kinase C activity in smooth muscle cells.20,21 The mechanism of this inhibition appears to be related with a diminished phosphorylation of protein kinase C-α.