Sobierajska Katarzyna, Wawro Marta E, Niewiarowska Jolanta
Department of Molecular Cell Mechanisms, Medical University of Lodz, 92-215 Lodz, Poland.
Int J Mol Sci. 2022 Feb 13;23(4):2062. doi: 10.3390/ijms23042062.
Around 45% of deaths in the EU and the US are due to fibrotic diseases. Although myofibroblasts are detected in various fibrotic tissues, they are mostly transdifferentiated from endothelial cells during the endothelial-mesenchymal transition (EndMT) induced by tumor growth factor-beta (TGF-β) family members. Growing evidence indicates that oxidative stress might enhance the sensitivity and the effects of TGF-β stimulation; however, the molecular mechanisms involved in the coordination of oxidative stress and TGF-β inductions remain poorly understood. Our findings indicate for the first time that oxidative stress enhances mesenchymal trans-differentiation of human microvascular endothelial cells (HMEC-1 cells) and that the oxidative stress-dependent TGF-β2-RhoA/Rac1-MRTF-A axis is critical for the induction of later stages of EndMT. This additive effect was manifested in TGF-β1-stimulated and Snail-overexpressed cells, where it caused higher cell elongation and faster migration on collagen I layers. Additionally, Western blot assay indicated the presence of alterations in cell contraction and EndMT markers. We conclude that complex anti-fibrotic therapies based on the inhibition of MRTF activities and oxidative stress might be an attractive target for fibrosis treatment.
在欧盟和美国，约45%的死亡是由纤维化疾病导致的。尽管在各种纤维化组织中都能检测到肌成纤维细胞，但它们大多是在肿瘤生长因子-β（TGF-β）家族成员诱导的内皮-间充质转化（EndMT）过程中从内皮细胞转分化而来的。越来越多的证据表明，氧化应激可能会增强TGF-β刺激的敏感性和效应；然而，氧化应激与TGF-β诱导之间协同作用的分子机制仍知之甚少。我们的研究结果首次表明，氧化应激会增强人微血管内皮细胞（HMEC-1细胞）的间充质转分化，并且氧化应激依赖性的TGF-β2-RhoA/Rac1-MRTF-A轴对于EndMT后期阶段的诱导至关重要。这种累加效应在TGF-β1刺激和Snail过表达的细胞中表现出来，在这些细胞中，它导致细胞在I型胶原层上的伸长更高且迁移更快。此外，蛋白质印迹分析表明细胞收缩和EndMT标志物存在变化。我们得出结论，基于抑制MRTF活性和氧化应激的复杂抗纤维化疗法可能是纤维化治疗的一个有吸引力的靶点。
