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(Circulation Research. 2003;92:104.)
© 2003 American Heart Association, Inc.

Molecular Medicine

-Tocopherol Induces Expression of Connective Tissue Growth Factor and Antagonizes Tumor Necrosis Factor-–Mediated Downregulation in Human Smooth Muscle Cells

Luis Villacorta^*, Aurélio V. Graça-Souza^*, Roberta Ricciarelli^*, Jean-Marc Zingg, Angelo Azzi

From the Department of Medical Biochemistry (A.V.G.-S.), Institute of Biomedical Sciences, Federal University of Rio de Janeiro-RJ, Brazil; Dip. Medicina Sperimentale (R.R.), University of Genova, Italy; and the Institute of Biochemistry and Molecular Biology (L.V., J.-M.Z., A.A.), University of Bern, Bern, Switzerland.

Correspondence to J.M. Zingg, PhD, Institut für Biochemie und Molekularbiologie, Universität Bern, Bühlstrasse 28, CH-3012 Bern, Switzerland. E-mail zingg{at}mci.unibe.ch

The effect of -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 -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 ß-tocopherol and N-acetylcysteine did not induce CTGF gene expression, suggesting a nonantioxidant mechanism for -tocopherol action. Protein kinase C (PKC) inhibition by -tocopherol has been previously described. However, PKC downregulation did not prevent CTGF induction by -tocopherol, and inhibition of PKC activity with several inhibitors did not increase its expression, suggesting an alternative pathway for the -tocopherol effect. On the other hand, tumor necrosis factor- reduced the expression of CTGF, an effect that was reversed by antioxidants. The data suggest that tumor necrosis factor- inhibition of CTGF gene expression is prevented in an antioxidant-sensitive process and that -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 -tocopherol may accelerate wound repair and tissue regeneration during atherosclerosis.

Key Words: connective tissue growth factor • okadaic acid • protein kinase C • -tocopherol • tumor necrosis factor-

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