Insulin-induced vascular endothelial growth factor expression is mediated by the NADPH oxidase NOX3
Insulin-induced vascular endothelial growth factor expression is mediated by the NADPH oxidase NOX3
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DOI：
10.1016/j.yexcr.2006.07.003
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发表时间：
2006-10-15
影响因子：
3.7
通讯作者：
Szanto, Ildiko
中科院分区：
文献类型：
--
作者：
Carnesecchi, Stephanie;Carpentier, Jean-Louis;Szanto, Ildiko
血管内皮生长因子(VEGF)是目前最有效的血管生成刺激因子。它的表达是由低氧条件下的活性氧(ROS)和常氧细胞中的胰岛素诱导的。ROS和胰岛素都可以激活丝裂原活化蛋白激酶(MAPKs)，诱导转录因子Sp1，这是血管内皮生长因子基因表达所必需的成分。本研究旨在探讨ROS产生NADPH氧化酶(NOX-ES)在胰岛素调节的血管内皮细胞生长因子(VEGF)基因激活中的作用。为了实现这一目标，我们选择了HepG2细胞作为我们的模型系统，因为这些细胞表达NADPH氧化酶亚型NOX3，并通过增强ROS的产生和血管内皮生长因子的mRNA转录和产生来响应胰岛素刺激。我们证明，在对照细胞中，胰岛素刺激导致过氧化氢的产生，p42/44MAPK的双相激活，以及Sp1和HIF-1α的诱导。NOX3特异性siRNA可抑制H_2O_2的产生，并特异性地抑制p42/44 MAPK的第二阶段磷酸化和Sp1 DNA结合，从而阻止血管内皮生长因子-A的表达上调。综上所述，我们的结果表明，NOX3是一种产生NADPH氧化酶的ROS，在胰岛素诱导的p42/44MAPK信号传递和VEGF-A产生中起着不可或缺的作用。(C)2006 Elsevier Inc.保留所有权利。
Vascular endothelial growth factor (VEGF) is the most potent stimulatory factor of angiogenesis. Its expression is induced by reactive oxygen species (ROS) in hypoxic conditions and by insulin in normoxic cells. Both ROS and insulin can activate mitogen-activated protein kinases (MAPKs) and induce the transcriptional factor Sp1, components that are essential for VEGF gene expression. The aim of this study was to investigate the role of ROS producing NADPH oxidase enzymes (NOX-es) in insulin-regulated VEGF gene activation. To achieve this goal we chose HepG2 cells as our model system as these cells express the NADPH oxidase isoform NOX3 and respond to insulin stimulation with enhanced ROS production and mRNA transcription and production of VEGF. We demonstrate that in control cells insulin stimulation leads to H2O2 generation, a biphasic activation of p42/44 MAPK and the induction of both Sp1 and HIF-1 alpha. Transfection of NOX3-specific siRNA abrogates H2O2 production and inhibits exclusively the second phase of p42/44 MAPK phosphorylation and Sp1 DNA binding and thus prevents upregulation of VEGF-A mRNA expression. In conclusion, our results demonstrate that NOX3, a ROS generating NADPH oxidase, plays an integral role in insulin-induced p42/44 MAPK signal transmission and VEGF-A production. (c) 2006 Elsevier Inc. All rights reserved.