The effect of alpha-tocopherol treatment on gene expression in human aortic vascular smooth muscle cells was analyzed by gene expression arrays. The expression of the connective tissue growth factor (CTGF) gene was induced by alpha-tocopherol 1.8-fold in gene array experiments, and similar results were also obtained by RT-PCR (1.7-fold) and at the protein level (1.4-fold). The antioxidants beta-tocopherol and N-acetylcysteine did not induce CTGF gene expression, suggesting a nonantioxidant mechanism for alpha-tocopherol action. Protein kinase C (PKC) inhibition by alpha-tocopherol has been previously described. However, PKC downregulation did not prevent CTGF induction by alpha-tocopherol, and inhibition of PKC activity with several inhibitors did not increase its expression, suggesting an alternative pathway for the alpha-tocopherol effect. On the other hand, tumor necrosis factor-alpha reduced the expression of CTGF, an effect that was reversed by antioxidants. The data suggest that tumor necrosis factor-alpha inhibition of CTGF gene expression is prevented in an antioxidant-sensitive process and that alpha-tocopherol increases CTGF expression by a PKC-independent, nonantioxidant mechanism. Because CTGF stimulates the synthesis of extracellular matrix, the normalization of CTGF gene expression by alpha-tocopherol may accelerate wound repair and tissue regeneration during atherosclerosis.