Kindlin-2 Mediates Mechanical Activation of Cardiac Myofibroblasts.
Kindlin-2 Mediates Mechanical Activation of Cardiac Myofibroblasts.
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作者：
Godbout E;Son DO;Hume S;Boo S;Sarrazy V;Clément S;Kapus A;Wehrle-Haller B;Bruckner-Tuderman L;Has C;Hinz B
我们发现粘着斑蛋白Kindlin-2参与了一种新的机械转导途径，该途径控制纤维化的心脏成纤维细胞到肌成纤维细胞的激活。Kindlin-2与肌成纤维细胞标记物α-平滑肌肌动蛋白(α-SMA)在纤维化大鼠心脏和暴露于纤维化僵硬培养底物和促纤维化转化生长因子-β1的人心脏成纤维细胞中共同上调。使用铁磁性微珠、可拉伸硅胶膜和细胞收缩激动剂对成纤维细胞施加压力，都会导致Kindlin-2移位到细胞核。过表达全长Kindlin-2而不是缺少一个可能的核定位序列(∆NLS kindlin-2)的Kindlin-2会导致α-SMA启动子活性增加。用小干扰RNA下调kindlin-2可导致肌成纤维细胞收缩减少和α-SMA表达减少，这依赖于α-SMA启动子中富含CC(A/T)的GG(Carg)盒元件。在Kindlin-2基因敲除下丢失的肌成纤维细胞特征可以被野生型拯救，但不能被∆NLS Kindlin-2挽救，这表明Kindlin-2控制的肌成纤维细胞需要它的核转位。由于Kindlin-2可以作为一个机械转导分子调节α-SMA的转录，因此它是一个潜在的干预组织纤维化中肌成纤维细胞激活的靶点。
We identify the focal adhesion protein kindlin-2 as player in a novel mechanotransduction pathway that controls profibrotic cardiac fibroblast to myofibroblast activation. Kindlin-2 is co-upregulated with the myofibroblast marker α-smooth muscle actin (α-SMA) in fibrotic rat hearts and in human cardiac fibroblasts exposed to fibrosis-stiff culture substrates and pro-fibrotic TGF-β1. Stressing fibroblasts using ferromagnetic microbeads, stretchable silicone membranes, and cell contraction agonists all result in kindlin-2 translocation to the nucleus. Overexpression of full-length kindlin-2 but not of kindlin-2 missing a putative nuclear localization sequence (∆NLS kindlin-2) results in increased α-SMA promoter activity. Downregulating kindlin-2 with siRNA leads to decreased myofibroblast contraction and reduced α-SMA expression, which is dependent on CC(A/T)-rich GG(CArG) box elements in the α-SMA promoter. Lost myofibroblast features under kindlin-2 knockdown are rescued with wild-type but not ∆NLS kindlin-2, indicating that myofibroblast control by kindlin-2 requires its nuclear translocation. Because kindlin-2 can act as a mechanotransducer regulating the transcription of α-SMA, it is a potential target to interfere with myofibroblast activation in tissue fibrosis.
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DOI：
10.1083/jcb.201701176
发表时间：
2017-11-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Böttcher RT;Veelders M;Rombaut P;Faix J;Theodosiou M;Stradal TE;Rottner K;Zent R;Herzog F;Fässler R
通讯作者：
Fässler R
DOI：
10.1038/nrm3112
发表时间：
2011-05
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.8
作者：
Brahme, Nina N.;Harburger, David S.;Calderwood, David A.
通讯作者：
Calderwood, David A.
影响因子：
4.8
作者：
D'Addario, M;Arora, PD;McCulloch, CAG
通讯作者：
McCulloch, CAG
影响因子：
20.1
作者：
Gan, Qiong;Yoshida, Tadashi;Owens, Gary K.
通讯作者：
Owens, Gary K.