Fibroblast growth factor represses Smad-mediated myofibroblast activation in aortic valvular interstitial cells.
Fibroblast growth factor represses Smad-mediated myofibroblast activation in aortic valvular interstitial cells.
复制标题
DOI：
10.1096/fj.07-087627
复制
发表时间：
2008-06
期刊：
影响因子：
4.8
通讯作者：
Anseth, Kristi S.
中科院分区：
文献类型：
--
作者：
Cushing, Melinda C.;Mariner, Peter D.;Liao, Jo-Tsu;Sims, Evan A.;Anseth, Kristi S.
本研究旨在确定在主动脉瓣中对抗结缔组织纤维化的信号通路。利用从猪主动脉瓣叶分离出的瓣膜间质细胞（VICs），我们发现碱性成纤维细胞生长因子（FGF - 2）能有效阻断转化生长因子 - β1（TGF - β1）介导的肌成纤维细胞活化。FGF - 2可阻止α - 平滑肌肌动蛋白（αSMA）表达的诱导以及VICs从细胞周期中退出，这两者都是肌成纤维细胞活化的标志。通过阻断作为TGF - β1下游核效应因子的Smad转录因子的活性，FGF - 2处理抑制了VICs中的纤维化。利用一种外源性Smad反应性转录启动子报告基因，我们发现Smad活性被FGF - 2抑制，这可能是因为FGF - 2处理阻止了这些细胞中Smads的核定位。这似乎是FGF通过丝裂原活化蛋白激酶（MAPK）级联信号传导的直接作用，因为用MAPK/细胞外调节激酶（MEK）抑制剂U0126处理VICs会诱导纤维化，并阻断FGF - 2抑制TGF - β1信号传导的能力。此外，FGF - 2处理VICs可阻止病理性收缩和钙化表型的发展，这表明这些通路可用于构建治疗瓣膜疾病的有效方法。——库欣，M. C.；马里纳，P. D.；廖，J. T.；西姆斯，E. A.；安塞斯，K. S. 成纤维细胞生长因子抑制主动脉瓣瓣膜间质细胞中Smad介导的肌成纤维细胞活化
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 α-smooth muscle actin (αSMA) 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.
登录
查看更多内容
影响因子：
6.9
作者：
Cushing, MC;Liao, JT;Anseth, KS
通讯作者：
Anseth, KS
影响因子：
4.6
作者：
Jian, B;Narula, N;Levy, RJ
通讯作者：
Levy, RJ
影响因子：
27.4
作者：
Mattey, DL;Dawes, PT;Slater, H
通讯作者：
Slater, H
影响因子：
2.4
作者：
Merryman, WD;Huang, HYS;Sacks, MS
通讯作者：
Sacks, MS
DOI：
10.1016/s0022-2828(87)80529-1
发表时间：
1987-12-01
影响因子：
5
作者：
JOHNSON, CM;HANSON, MN;HELGESON, SC
通讯作者：
HELGESON, SC