Akt1 Mediates α-Smooth Muscle Actin Expression and Myofibroblast Differentiation via Myocardin and Serum Response Factor
Akt1 Mediates α-Smooth Muscle Actin Expression and Myofibroblast Differentiation via Myocardin and Serum Response Factor
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DOI：
10.1074/jbc.m113.504290
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发表时间：
2013-11-15
影响因子：
4.8
通讯作者：
Somanath, Payaningal R.
中科院分区：
文献类型：
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作者：
Abdalla, Maha;Goc, Anna;Somanath, Payaningal R.
肌成纤维细胞（MF）分化以平滑肌肌动蛋白（SMA）应力纤维的从头表达为标志，在伤口愈合中起核心作用，并且其持续性是纤维化疾病的标志。我们以前已经表明，Akt 1是通过基质调节伤口愈合所必需的。然而，Akt 1在调节MF分化中的作用及其在纤维化中的意义仍然不清楚。在这里，我们发现Akt 1的持续激活与SMA表达和组装的6倍增加相关;尽管TGF刺激，但在表达非活性Akt 1的细胞中，这种作用是钝化的。从机制上讲，Akt 1通过收缩基因转录因子myocardin和血清反应因子（SRF）介导TGF诱导的SMA合成，独立于小鼠胚胎成纤维细胞和过表达活性Akt 1的成纤维细胞中雷帕霉素的哺乳动物靶点。Akt 1缺陷与体内心肌素、SRF和SMA表达降低相关。此外，持续的Akt 1诱导的SMA合成显着减少后，RNA沉默的SRF和myocardin。除了其在SMA合成中不可或缺的作用外，我们还表明Akt 1介导MF分化所需的纤连蛋白剪接变体表达，以及总纤连蛋白，其产生促进MF分化的收缩力。总之，我们的研究结果构成的证据表明，持续的Akt 1激活是至关重要的TGF-诱导的MF的形成和持续分化。这些发现突出了Akt 1作为纤维化疾病的新的潜在治疗靶点。
Myofibroblast (MF) differentiation, marked by the de novo expression of smooth muscle -actin (SMA) stress fibers, plays a central role in wound healing and its persistence is a hallmark of fibrotic diseases. We have previously shown that Akt1 is necessary for wound healing through matrix regulation. However, the role of Akt1 in regulating MF differentiation with implications in fibrosis remains poorly defined. Here, we show that sustained activation of Akt1 was associated with a 6-fold increase in SMA expression and assembly; an effect that is blunted in cells expressing inactive Akt1 despite TGF stimulation. Mechanistically, Akt1 mediated TGF-induced SMA synthesis through the contractile gene transcription factors myocardin and serum response factor (SRF), independent of mammalian target of rapamycin in mouse embryonic fibroblasts and fibroblasts overexpressing active Akt1. Akt1 deficiency was associated with decreased myocardin, SRF, and SMA expressions in vivo. Furthermore, sustained Akt1-induced SMA synthesis markedly decreased upon RNA silencing of SRF and myocardin. In addition to its integral role in SMA synthesis, we also show that Akt1 mediates fibronectin splice variant expression, which is required for MF differentiation, as well as total fibronectin, which generates the contractile force that promotes MF differentiation. In summary, our results constitute evidence that sustained Akt1 activation is crucial for TGF-induced MF formation and persistent differentiation. These findings highlight Akt1 as a novel potential therapeutic target for fibrotic diseases.