Fibrosis is perpetuated by an autocrine, pro-adhesive signaling loop maintained by the synthetic and contractile abilities of myofibroblasts and the stiff, highly-crosslinked extracellular matrix. Transcriptional complexes that are exquisitely responsive to mechanotransduction include the co-activator YAP1, which regulates the expression of members of the CCN family of matricellular proteins such as CCN2 and CCN1. Although selective YAP1 inhibitors exist, the effect of these inhibitors on profibrotic gene expression in fibroblasts is largely unknown, and is the subject of our current study. Herein, we use genome-wide expression profiling, real-time polymerase chain reaction and Western blot analyses, cell migration and collagen gel contraction assays to assess the ability of a selective YAP inhibitor verteporfin (VP) to block fibrogenic activities in dermal fibroblasts from healthy individual human controls and those from isolated from fibrotic lesions of patients with diffuse cutaneous systemic sclerosis (dcSSc). In control fibroblasts, VP selectively reduced expression of fibrogenic genes and also blocked the ability of TGFbeta to induce actin stress fibers in dermal fibroblasts. VP also reduced the persistent profibrotic phenotype of dermal fibroblasts cultured from fibrotic lesions of patients with dcSSc. Our results are consistent with the notion that, in the future, YAP1 inhibitors may represent a novel, valuable method of treating fibrosis as seen in dcSSc.

纤维化由成肌纤维细胞和坚硬的，高度交联的细胞外基质的合成和收缩能力所维持的自分泌，促粘附信号循环所持久。对机械转导非常敏感的转录复合物包括共激活因子YAP1，它调节母细胞蛋白CCN家族成员（如CCN2和CCN1）的表达。尽管存在选择性的YAP1抑制剂，但这些抑制剂对成纤维细胞中促纤维化基因表达的影响尚不清楚，这是我们当前研究的主题。在这里，我们使用全基因组表达谱分析，实时聚合酶链反应和Western印迹分析，细胞迁移和胶原蛋白凝胶收缩试验，以评估选择性YAP抑制剂维替泊芬（VP）阻断来自健康个体人类对照以及从患有弥漫性皮肤系统性硬化症（dcSSc）的患者的纤维化病变中分离出的真皮成纤维细胞中的成纤维细胞活性。在对照成纤维细胞中，VP选择性降低了成纤维基因的表达，并且还阻断了TGFbeta诱导真皮成纤维细胞中肌动蛋白应激纤维的能力。VP还减少了从dcSSc患者的纤维化病灶培养的皮肤成纤维细胞的持久纤维化表型。我们的结果与以下观点一致：在将来，YAP1抑制剂可能代表一种新颖的，有价值的治疗纤维化的方法，如dcSSc中所见。