Published online before print December 2, 2002, doi: 10.1161/01.RES.0000049103.38175.1B
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Submitted on July 26, 2002
Revised on October 29, 2002
Accepted on November 13, 2002
-Tocopherol Induces Expression of Connective Tissue Growth Factor and Antagonizes Tumor Necrosis Factor--Mediated Downregulation in Human Smooth Muscle Cells
Luis Villacorta ;
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.
* To whom correspondence should be addressed. 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 
-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 • gene expression regulation • okadaic acid • protein kinase C •
-tocopherol •
tumor necrosis factor-
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