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This Article Full Text Full Text (PDF) All Versions of this Article: fj.07-087627v1 22/6/1769    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Cushing, M. C. Articles by Anseth, K. S. PubMed PubMed Citation Articles by Cushing, M. C. Articles by Anseth, K. S.

Fibroblast growth factor represses Smad-mediated myofibroblast activation in aortic valvular interstitial cells

Melinda C. Cushing^*, Peter D. Mariner^*,, Jo-Tsu Liao^*, Evan A. Sims^* and Kristi S. Anseth^*,,1

^* Department of Chemical and Biological Engineering; and

Howard Hughes Medical Institute, University of Colorado, Boulder, Colorado, USA

¹Correspondence: University of Colorado, Department of Chemical and Biological Engineering, ECCH 111, UCB 424, Boulder, CO 80309-0424, USA. E-mail: kristi.anseth{at}colorado.edu

This study aimed to identify signaling pathways that oppose connective tissue fibrosis in the aortic valve. Using valvular interstitial cells (VICs) isolated from porcine aortic valve leaflets, we show that basic fibroblast growth factor (FGF-2) effectively blocks transforming growth factor-β1 (TGF-β1)-mediated myofibroblast activation. FGF-2 prevents the induction of -smooth muscle actin (SMA) expression and the exit of VICs from the cell cycle, both of which are hallmarks of myofibroblast activation. By blocking the activity of the Smad transcription factors that serve as the downstream nuclear effectors of TGF-β1, FGF-2 treatment inhibits fibrosis in VICs. Using an exogenous Smad-responsive transcriptional promoter reporter, we show that Smad activity is repressed by FGF-2, likely an effect of the fact that FGF-2 treatment prevents the nuclear localization of Smads in these cells. This appears to be a direct effect of FGF signaling through mitogen-activated protein kinase (MAPK) cascades as the treatment of VICs with the MAPK/extracellular regulated kinase (MEK) inhibitor U0126 acted to induce fibrosis and blocked the ability of FGF-2 to inhibit TGF-β1 signaling. Furthermore, FGF-2 treatment of VICs blocks the development of pathological contractile and calcifying phenotypes, suggesting that these pathways may be utilized in the engineering of effective treatments for valvular disease.—Cushing, M. C., Mariner, P. D., Liao, J. T., Sims, E. A., Anseth, K. S. Fibroblast growth factor represses Smad-mediated myofibroblast activation in aortic valvular interstitial cells.

Key Words: transforming growth factor-β1 • heart disease • -smooth muscle actin • cell signaling