Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Ultrasound, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
J Cell Physiol. 2019 Jun;234(6):9052-9064. doi: 10.1002/jcp.27583. Epub 2018 Oct 30.
Endothelial-to-mesenchymal transition (EndMT) was first reported in heart development. Recent studies have shown that EndMT also occurs in the progression of cardiac fibrosis. Herein, we demonstrated a critical role of the Forkhead Box M1 (Foxm1) transcription factor in transforming growth factor beta (TGF-β)-induced EndMT in endothelial cells (ECs) and a possible underlying molecular mechanism. Foxm1 was induced in ECs following TGF-β stimulation. Using both pharmacological and molecular approaches to inhibit Foxm1 function can attenuate the TGF-β-induced EndMT and cell migration. In contrast, lentivirus-mediated overexpression of Foxm1 allowed EndMT to proceed despite the absence of TGF-β in ECs. Moreover, we found that the activation of the Smad2/3 signaling pathway and EndMT-related transcription factors played important roles in the pathogenesis of Foxm1-mediated EndMT. Further analysis revealed that Foxm1 bound to and increased the promoter activity of the Snail gene encoding a critical transcriptional regulator of EndMT. In conclusion, our results identify FOXM1 as a driver of TGF-β-induced EndMT and underscore the therapeutic potential of targeting FOXM1 for cardiac fibrosis.
内皮细胞向间充质细胞转变（EndMT）最初在心脏发育中被报道。最近的研究表明，EndMT 也发生在心脏纤维化的进展中。在此，我们证明了叉头框转录因子 M1（Foxm1）在转化生长因子-β（TGF-β）诱导的内皮细胞（ECs）EndMT 中的关键作用及其潜在的分子机制。TGF-β刺激后，Foxm1 在 ECs 中被诱导。使用药理学和分子方法抑制 Foxm1 功能可以减弱 TGF-β诱导的 EndMT 和细胞迁移。相反，尽管 ECs 中缺乏 TGF-β，慢病毒介导的 Foxm1 过表达也允许 EndMT 进行。此外，我们发现 Smad2/3 信号通路的激活和 EndMT 相关转录因子在 Foxm1 介导的 EndMT 的发病机制中发挥重要作用。进一步分析表明，Foxm1 结合并增加了编码 EndMT 关键转录调节剂的 Snail 基因的启动子活性。总之，我们的结果确定 FOXM1 是 TGF-β 诱导的 EndMT 的驱动因素，并强调了针对 FOXM1 治疗心脏纤维化的潜在治疗意义。
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