on February 9, 2006
Published online before print February 9, 2006, doi: 10.1161/01.ATV.0000209517.00220.cd
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Submitted on October 11, 2005
Accepted on January 24, 2006
PKC
Is Necessary for Smad3 Expression and Transforming Growth Factor 
-Induced Fibronectin Synthesis in Vascular Smooth Muscle Cells
Evan J. Ryer ;
From the Division of Vascular Surgery (E.J.R., R.P.H., K.S., P.L.F., B.L., K.C.K.), New York Presbyterian Hospital, Cornell University, Weill Medical School and Columbia University, College of Physicians and Surgeons, New York, NY; the Department of Molecular and Cellular Biology (K.I.N.), Medical Institute of Bioregulation, Kyushu University, Japan; and the Department of Developmental Biology (K.N.), Graduate School of Medicine, Tohoku University School of Medicine, Japan.
* To whom correspondence should be addressed. E-mail: kckent{at}med.cornell.edu.
Objective--The purpose of these studies is to investigate the mechanism by which transforming growth factor (TGF)
1 regulates the synthesis of the extracellular matrix protein fibronectin (FN).
Methods and Results--TGF1 elicited a time-dependent induction of FN protein and mRNA in A10 rat aortic smooth muscle cells (SMCs). Ectopic expression of Smad3 in A10 cells stimulated both basal and TGF1-induced FN expression, whereas expression of Smad7 eliminated the TGF response. Because TGF activated PKC
in SMCs, we tested the role of PKC in regulation of FN expression. Inhibition of PKC activity by rottlerin or dominant-negative adenovirus (AdPKC DN) blocked TGF1’s induction of FN, whereas overexpression of PKC enhanced TGF’s effect. Moreover, aortic SMCs isolated from PKC-/- mice exhibited diminished FN induction in response to TGF. Furthermore, we found that Smad3 protein and mRNA were markedly reduced in AdPKC DN-treated A10 cells and in PKC null cells. Finally, restoring Smad3 in rottlerin-treated A10 and PKC null cells rescues the ability of TGF to upregulate FN expression.
Conclusion--Our data suggest that TGF-activated PKC is critical to maintain normal expression of Smad3, which in turn is required for the induction of fibronectin. PKC represents a promising target for treating the fibroproliferative response after arterial injury.
Key words: extracellular matrix • fibronectin • intimal hyperplasia • protein kinase C delta • TGF beta
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