Upregulation of the actin cytoskeleton via myocardin leads to increased expression of type 1 collagen.
Upregulation of the actin cytoskeleton via myocardin leads to increased expression of type 1 collagen.
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DOI：
10.1038/labinvest.2017.96
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发表时间：
2017-12
期刊：
影响因子：
--
通讯作者：
Rockey DC
中科院分区：
文献类型：
--
作者：
Shi Z;Rockey DC
肝纤维化的特征是细胞外基质（ECM）在肝脏中的过度沉积。虽然许多纤维化细胞类型可以表达ECM，但目前认为肝星状细胞（HSC）是主要的效应细胞。HSC在称为活化的过程中转化为肌成纤维细胞样细胞，也称为肝肌成纤维细胞;该过程的特征特别是平滑肌α肌动蛋白（SM α-actin）和1型胶原蛋白的从头表达。肌动蛋白家族形成细胞骨架，在许多细胞过程中是必不可少的。β-肌动蛋白和细胞质γ-肌动蛋白（γ-肌动蛋白）广泛表达，而SM α-肌动蛋白定义了平滑肌细胞和肌成纤维细胞表型。因此，SM α-actin与多种功能特性紧密相关。然而，肌动蛋白亚型可能调节1型胶原的调节机制仍不清楚。在正常和纤维化大鼠肝脏的原代HSC中，我们证明了心肌素（一种典型的SRF辅因子）在肝肌成纤维细胞中上调，并分别通过激活SM α-肌动蛋白启动子中的ATTA盒和γ-肌动蛋白和β-肌动蛋白启动子中的CCAAT盒来差异调节SM α-肌动蛋白、γ-肌动蛋白和β-肌动蛋白;此外，心肌素差异激活肌动蛋白启动子的CArG盒中的血清反应因子（SRF）。此外，心肌素刺激Smad 2磷酸化和RhoA表达，导致肌动蛋白细胞骨架依赖性方式的1型胶原表达增加。Myocardin还直接增强SRF表达并刺激胶原1α1和1α2启动子活性。此外，在四氯化碳诱导的肝损伤过程中，体内心肌素的过度表达导致HSC活化和纤维化增加。总之，我们的数据表明，myocardin在HSC活化过程中的肌动蛋白细胞骨架动力学中起着关键作用，反过来，特异性地调节肝肌成纤维细胞中I型胶原的表达。
Liver fibrosis is characterized by excessive deposition of extracellular matrix (ECM) in the liver. Although many fibrogenic cell types may express ECM, the hepatic stellate cell (HSC) is currently considered to be the major effector. HSCs transform into myofibroblast-like cells, also known as hepatic myofibroblasts in a process known as activation; this process is characterized in particular by de novo expression of smooth muscle alpha actin (SM α-actin) and type 1 collagen. The family of actins, which form the cell’s cytoskeleton, are essential in many cellular processes. β-actin and cytoplasmic γ-actin (γ-actin) are ubiquitously expressed, while SM α-actin defines smooth muscle cell and myofibroblast phenotypes. Thus, SM α-actin is tightly associated with multiple functional properties. However, the regulatory mechanisms by which actin isoforms might regulate type 1 collagen remain unclear. In primary HSCs from normal and fibrotic rat liver, we demonstrate that myocardin, a canonical SRF cofactor, is upregulated in hepatic myofibroblasts and differentially regulates SM α-actin, γ-actin and β actins through activation of an ATTA box in the SM α-actin and a CCAAT box in γ-actin and β actin promoters, respectively; moreover, myocardin differentially activated serum response factor (SRF) in CArG boxes of actin promoters. Additionally, myocardin stimulated Smad2 phosphorylation and RhoA expression, leading to increased expression of type 1 collagen in an actin cytoskeleton dependent manner. Myocardin also directly enhanced SRF expression and stimulated collagen 1α1 and 1α2 promoter activities. Additionally, overexpression of myocardin in vivo during carbon tetrachloride-induced liver injury led to increased HSC activation and fibrogenesis. In summary, our data suggest that myocardin plays a critical role in actin cytoskeletal dynamics during HSC activation, in turn, specifically regulating type I collagen expression in hepatic myofibroblasts.
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