We studied the effects of RRR-alpha-tocopherol and RRR-beta-tocopherol in smooth muscle cells from rat (line A7r5) and human aortas. RRR-alpha-Tocopherol, but not RRR-beta-tocopherol, inhibited smooth muscle cell proliferation in a dose-dependent manner at concentrations in the range from 10 to 50 mumol/L. RRR-beta-Tocopherol added simultaneously with RRR-alpha-tocopherol prevented growth inhibition. The earliest event brought about by RRR-alpha-tocopherol in the signal transduction cascade controlling receptor-mediated cell growth was the activation of the transcription factor AP-1. RRR-beta-tocopherol alone was without effect but in combination with RRR-alpha-tocopherol prevented the AP-1 activating effect of the latter. Protein kinase C was inhibited by RRR-alpha-tocopherol and not by RRR-beta-tocopherol, which also in this case prevented the effect of RRR-alpha-tocopherol. Calyculin A, a protein phosphatase inhibitor, prevented the effect of RRR-alpha-tocopherol on protein kinase C. The data can be rationalized by a model in which a tocopherol-binding protein discriminates between RRR-alpha-tocopherol and RRR-beta-tocopherol and initiates a cascade of events at the level of cell signal transduction that leads to the inhibition of cell proliferation.

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α‐Tocopherol, but not β‐tocopherol, negatively regulates proliferation of A7r5 vascular smooth muscle cells at physiological concentration. The HeLa cell line was not affected whereas the Chinese hamster ovary cell line (CHO) was slightly inhibited by both α‐tocopherol and β‐tocopherol. In A7r5 cells α‐tocopherol inhibited protein kinase C activity, and this correlated with inhibition of proliferation. β‐Tocopherol did not inhibit either protein kinase C or proliferation. In HeLa cells no inhibition by α‐tocopherol or β‐tocopherol of protein kinase C activity and cell proliferation was observed. In Chinese hamster ovary cells both tocopherols inhibited protein kinase C activity but not proliferation. Thus in the latter cells proliferation was not protein kinase C‐dependent. In A7r5 cells α‐tocopherol but not β‐tocopherol activated AP‐l‐mediated gene expression. In HeLa cells no change in gene expression was observed in agreement with the finding that also protein kinase C was not affected. In CHO cells gene expression was activated by both α‐tocopherol and β‐tocopherol. In this case also a positive correlation was found with similar inhibition of protein kinase C activity. In these cells, however, the changes at the level of protein kinase C activity and gene expression did not result in proliferation changes. The effect of α‐tocopherol and β‐tocopherol on protein kinase C activity and gene expression suggest a cause‐to‐effect relationship. Inhibition of proliferation, however, correlates in the case of A7r5 and HeLa cells but not in the case of CHO suggesting a different proliferation pathway for these cells.