Inhibition of Notch signaling leads to increased intracellular ROS by up-regulating Nox4 expression in primary HUVECs
Inhibition of Notch signaling leads to increased intracellular ROS by up-regulating Nox4 expression in primary HUVECs
复制标题
抑制 Notch 信号传导可通过上调原代 HUVEC 中的 Nox4 表达来增加细胞内 ROS。
DOI：
10.1016/j.cellimm.2013.12.009
复制
发表时间：
2014-02-01
影响因子：
4.3
通讯作者：
Zhang, Ping
中科院分区：
文献类型：
--
作者：
Cai, Wei-Xia;Liang, Liang;Zhang, Ping
Notch通路在血管生成中的重要作用已被报道多年。然而，Notch通路如何在调节内皮细胞中发挥作用仍然很大程度上未知。在这项研究中，我们发现，阻断Notch信号与γ-分泌酶抑制剂增加活性氧在原代人脐静脉内皮细胞（HUVECs）在正常和缺血/再灌注（I/R）条件下。用ROS清除剂或ROS产生的特异性抑制剂阻断HUVEC中ROS的产生可阻断Notch阻断诱导的HUVEC增殖、迁移和粘附，提示Notch通路对内皮细胞行为的调节至少部分依赖于其下调ROS水平。我们进一步表明，阻断Notch信号后ROS的产生增加伴随着Nox 4的表达增加，这导致HUVEC中VEGFR 2和ERK的磷酸化增加。总之，我们的研究结果表明，Notch信号通过抑制Nox 4来调节ROS的产生，并进一步调节内皮细胞的增殖、迁移和粘附。(C)2014爱思唯尔公司All rights reserved.
The essential roles of Notch pathway in angiogenesis have been reported for years. However, how Notch pathway plays its role in regulating endothelial cells remains largely unknown. In this study we found that blockade of Notch signaling with a gamma-secretase inhibitor increased reactive oxygen species (ROS) in primary human umbilical vein endothelial cells (HUVECs) under both normaxic and ischemia/reperfusion (I/R) conditions. Abruption of ROS generation with ROS scavengers or specific inhibitors of ROS production in HUVECs abolished Notch blockade-induced HUVEC proliferation, migration and adhesion, suggesting that the regulation of Notch pathway on endothelial cell behavior is at least partially dependent on its down-regulation of ROS level. We further showed that the enhanced generation of ROS after blocking Notch signal was accompanied by augmented expression of Nox4, which led to increased phosphorylation of VEGFR2 and ERK in HUVECs. In summary, our results have shown that Notch signaling regulates ROS generation by suppressing Nox4, and further modulates endothelial cell proliferation, migration and adhesion. (C) 2014 Elsevier Inc. All rights reserved.