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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:780.)
© 2006 American Heart Association, Inc.

Vascular Biology

PKC Is Necessary for Smad3 Expression and Transforming Growth Factor ß–Induced Fibronectin Synthesis in Vascular Smooth Muscle Cells

Evan J. Ryer; R. Patrick Hom; Kenji Sakakibara; Keiichi I. Nakayama; Keiko Nakayama; Peter L. Faries; Bo Liu; K. Craig Kent

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.

Correspondence to K. Craig Kent, MD, Department of Surgery, New York Presbyterian Hospital, Weill Medical College, Cornell University, 525 E 68th St, Room 707, New York, NY 10021. E-mail kckent{at}med.cornell.edu

Objective— The purpose of these studies is to investigate the mechanism by which transforming growth factor (TGF)ß1 regulates the synthesis of the extracellular matrix protein fibronectin (FN).

Methods and Results— TGFß1 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 TGFß1-induced FN expression, whereas expression of Smad7 eliminated the TGFß response. Because TGFß 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 TGFß1’s induction of FN, whereas overexpression of PKC enhanced TGFß’s effect. Moreover, aortic SMCs isolated from PKC^–/– mice exhibited diminished FN induction in response to TGFß. 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 TGFß to upregulate FN protein and mRNA expression.

Conclusion— Our data suggest that TGFß-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.

The mechanism by which TGFß regulates the synthesis of fibronectin remains inconclusive. Our data suggest that TGFß-activated PKC is critical to maintain Smad3 levels, which in turn are required for fibronectin expression. Thus, PKC may serve as a novel therapeutic target to prevent the fibroproliferative response after arterial injury.

Key Words: extracellular matrix • fibronectin • intimal hyperplasia • protein kinase C delta • TGF beta

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