THE ROLE OF HYDROGEN-PEROXIDE AND RRR-ALPHA-TOCOPHEROL IN SMOOTH-MUSCLE CELL-PROLIFERATION

Oxidants can be considered early growth signals, since they have been shown to activate a number of pathways that are also stimulated by gro wth factors. In particular, H2O2 activates the protein kinase C signal transduction pathway in smooth muscle cells. These events certainly p lay a role in the activation of the DNA synthesis machinery although i t is still unclear whether they can also regulate the lethal response. Evidence exists of an oxidant-mediated increase in tyrosine protein p hosphorylation as an early event in the signal transduction cascade of growth factor receptors, leading to augmentation of cell proliferatio n. Oxidants can also induce transcription of enzymes, such as ornithin e decarboxylase and the phosphatase CL-100. CL-100 is the first exampl e of a new class of protein phosphatases responsible for modulating th e activation of MAP kinase following exposure of quiescent cells to gr owth factors and further implicates MAP kinase activation/ deactivatio n in the cellular response to hydrogen peroxide. Moreover H2O2 activat es the MAP kinase cascade by stimulating the tyrosine kinase and prote in kinase C pathways. JNK1, a relative of the MAP kinase group, is act ivated by dual phosphorylation at Thr and Tyr during the UV response. RRR-alpha-tocopherol and RRR-beta-tocopherol have different and compet ing effects on smooth muscle cell proliferation, indicating that they do not act as antioxidants. The earliest event brought by RRR-alpha-to copherol in the signal transduction cascade contolling receptor mediat ed cell growth is the inhibition of the transcription factor AP-1, act ivated by phorbol esters. RRR-beta-tocopherol alone is without effect but in combination with RRR-alpha-tocopherol prevents the AP-1-inhibit ing effect of the latter. Protein kinase C is inhibited by RRR-alpha-t ocopherol and not by RRR-beta-tocopherol, which also in this case prev ented the effect of RRR-alpha-tocopherol. The inhibition of RRR-alpha- tocopherol of protein kinase C is not the consequence of a direct inte raction but is due to a diminution, produced by RRR-alpha-tocopherol o f the kinase phosphorylation. A tocopherol binding protein appears to be at the basis of the RRR-alpha-tocopherol,that discriminates between RRR-alpha-tocopherol and RRR-beta-tocopherol and initiates a cascade of events at the level of cell signal transduction leading to cell pro liferation inhibition.