What is the clinical evidence from this study?

Study design: Other. Population: Valvular fibrosis. Intervention: FGF-2 (basic fibroblast growth factor) vs. Untreated controls or TGF-β1 alone. Primary outcome: Myofibroblast activation (α-SMA expression, Smad activity, matrix deposition).

January 24, 2008The FASEB Journal139 citationsOpen Access

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

MCMelinda C. CushingOregon Health & Science University PMPeter D. MarinerUniversity of Colorado Boulder JLJo‐Tsu LiaoUniversity of Colorado Boulder

Key Result

FGF-2 effectively blocks TGF-β1-mediated myofibroblast activation in aortic valvular interstitial cells by preventing the nuclear localization of Smad transcription factors via a MAPK-dependent pathway.

PICO

Population

In vitro study using valvular interstitial cells isolated from porcine aortic valve leaflets to investigate signaling pathways opposing connective tissue fibrosis.

Intervention / Comparator

FGF-2 (basic fibroblast growth factor) vs Untreated controls or TGF-β1 alone (1-100 ng/ml)

Primary Outcome

Myofibroblast activation (α-SMA expression, Smad activity, matrix deposition)

Limitations

Further investigation into the responses of VICs to these pharmacological stimuli under externally applied mechanical stress is warranted.

Abstract

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-beta1 (TGF-beta1)-mediated myofibroblast activation. FGF-2 prevents the induction of alpha-smooth muscle actin (alphaSMA) 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-beta1, 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-beta1 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.

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Cite This Study

Cushing et al. (Thu,) conducted a other in Valvular fibrosis. FGF-2 (basic fibroblast growth factor) vs. Untreated controls or TGF-β1 alone was evaluated on Myofibroblast activation (α-SMA expression, Smad activity, matrix deposition). FGF-2 effectively blocks TGF-β1-mediated myofibroblast activation in aortic valvular interstitial cells by preventing the nuclear localization of Smad transcription factors via a MAPK-dependent pathway.

synapsesocial.com/papers/6a75ceb3b5de85d41819ca8b https://doi.org/https://doi.org/10.1096/fj.07-087627