PKCδ is necessary for Smad3 expression and transforming growth factor β-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

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)

Abstract

Objective - The purpose of these studies is to investigate the mechanism by which transforming growth factor (TGF)β1 regulates the synthesis of the extracellular matrix protein fibronectin (FN). Methods and Results - TGFβ1 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 TGFβ1-induced FN expression, whereas expression of Smad7 eliminated the TGFβ response. Because TGFβ activated PKCδ in SMCs, we tested the role of PKCδ in regulation of FN expression. Inhibition of PKCδ activity by rottlerin or dominant-negative adenovirus (AdPKCδ DN) blocked TGFβ1's induction of FN, whereas overexpression of PKCδ enhanced TGFβ's effect. Moreover, aortic SMCs isolated from PKCδ-/- mice exhibited diminished FN induction in response to TGFβ. Furthermore, we found that Smad3 protein and mRNA were markedly reduced in AdPKCδ DN-treated A10 cells and in PKCδ null cells. Finally, restoring Smad3 in rottlerin-treated A10 and PKCδ null cells rescues the ability of TGFβ to upregulate FN protein and mRNA expression. Conclusion - Our data suggest that TGFβ-activated PKCδ is critical to maintain normal expression of Smad3, which in turn is required for the induction of fibronectin. PKCδ represents a promising target for treating the fibroproliferative response after arterial injury.

Original languageEnglish
Pages (from-to)780-786
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume26
Issue number4
DOIs
Publication statusPublished - 2006 Apr

Keywords

  • Extracellular matrix
  • Fibronectin
  • Intimal hyperplasia
  • Protein kinase C delta
  • TGF beta

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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