Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway
Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway
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DOI：
10.1038/labinvest.2014.100
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发表时间：
2014-10-01
影响因子：
5
通讯作者：
Simon, Felipe
中科院分区：
文献类型：
--
作者：
Montorfano, Ignacio;Becerra, Alvaro;Simon, Felipe
在全身性炎症的发病过程中，活性氧（ROS）在血流中循环并与内皮细胞（EC）相互作用，增加细胞内的氧化应激。尽管内皮功能障碍在全身性炎症的发病机制中至关重要，但关于氧化应激对内皮功能障碍的影响知之甚少。氧化应激诱导多种功能，包括细胞转化。细胞转化的一个独特过程是腱皮向间充质转化，其中EC变成肌成纤维细胞，从而失去其内皮特性并获得纤维化行为。然而，参与氧化应激作为一个电感器的转换EC成肌成纤维细胞是未知的。因此，我们研究了氧化应激在这种转化中所起的作用，并研究了其潜在的机制。我们的研究结果表明，氧化应激通过降低内皮标志物的水平和增加纤维化和ECM蛋白的水平诱导EC转化为肌成纤维细胞。其潜在机制取决于ALK 5/Smad 3/NF-κ B途径。氧化应激诱导TGF-β 1和TGF-β 2的表达和分泌以及p38 MAPK磷酸化。通过siRNA技术下调TGF-β 1和TGF-β 2可消除H2 O2诱导的转化。据我们所知，这是第一份报告表明，氧化应激能够诱导转化为肌成纤维细胞通过TGF-β分泌的EC，作为氧化应激为基础的血管功能障碍的来源出现。因此，氧化应激是通过TGF-β依赖性机制诱导EC转化为神经成纤维细胞、改变EC蛋白表达谱以及将正常EC转化为病理性EC的决定性因素。这些信息将有助于设计新的和改进的治疗策略，对氧化应激介导的全身炎症性疾病。
During the pathogenesis of systemic inflammation, reactive oxygen species (ROS) circulate in the bloodstream and interact with endothelial cells (ECs), increasing intracellular oxidative stress. Although endothelial dysfunction is crucial in the pathogenesis of systemic inflammation, little is known about the effects of oxidative stress on endothelial dysfunction. Oxidative stress induces several functions, including cellular transformation. A singular process of cell conversion is tendothelial-to-mesenchymal transition, in which ECs become myofibroblasts, thus losing their endothelial properties and gaining fibrotic behavior. However, the participation of oxidative stress as an inductor of conversion of ECs into myofibroblasts is not known. Thus, we studied the role played by oxidative stress in this conversion and investigated the underlying mechanism. Our results show that oxidative stress induces conversion of ECs into myofibroblasts through decreasing the levels of endothelial markers and increasing those of fibrotic and ECM proteins. The underlying mechanism depends on the ALK5/Smad3/NF-kappa B pathway. Oxidative stress induces the expression and secretion of TGF-beta 1 and TGF-beta 2 and p38 MAPK phosphorylation. Downregulation of TGF-beta 1 and TGF-beta 2 by siRNA technology abolished the H2O2-induced conversion. To our knowledge, this is the first report showing that oxidative stress is able to induce conversion of ECs into myofibroblasts via TGF-beta secretion, emerging as a source for oxidative stress-based vascular dysfunction. Thus, oxidative stress emerges as a decisive factor in inducing conversion of ECs into nnyofibroblasts through a TGF-beta-dependent mechanism, changing the ECs protein expression profile, and converting normal ECs into pathological ones. This information will be useful in designing new and improved therapeutic strategies against oxidative stress-mediated systemic inflammatory diseases.