Peroxynitrite increases VEGF expression in vascular endothelial cells via STAT3
Peroxynitrite increases VEGF expression in vascular endothelial cells via STAT3
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DOI：
10.1016/j.freeradbiomed.2005.06.015
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发表时间：
2005-11-15
影响因子：
7.4
通讯作者：
Caldwell, RB
中科院分区：
文献类型：
--
作者：
Platt, DH;Bartoli, M;Caldwell, RB
在糖尿病微血管病变、肿瘤血管生成和动脉粥样硬化等多种疾病中，血管内皮生长因子(VEGF)的表达增加与氧化应激增加和过氧亚硝酸盐的形成有关。在这项研究中，我们检验了过氧亚硝酸盐刺激血管内皮生长因子表达的假设。外源性过氧亚硝酸根作用于微血管内皮细胞后，血管内皮细胞中VEGFmRNA的表达呈时间和剂量依赖性增加，在100mM作用1h内达到高峰，随后VEGFmRNA的表达和蛋白的表达均显著增加。为了明确过氧亚硝酸根对缺氧和肿瘤血管生成过程中调节血管内皮生长因子表达的两种转录因子--信号转导和转录激活子3(STAT3)和缺氧诱导因子-1(HIF-1)的激活作用，研究了过氧亚硝酸盐的作用机制。过氧亚硝酸盐引起STAT3的活化和核转位，但不引起HIF-1。此外，转导显性负性STAT3基因的内皮细胞可消除过氧亚硝酸盐诱导的血管内皮细胞生长因子基因表达的增加。转录抑制物也能抑制血管内皮细胞生长因子的表达，但对蛋白质合成的抑制作用不明显。这些结果表明，过氧亚硝酸盐通过激活STAT3引起血管内皮细胞中血管内皮细胞生长因子表达增加。(C)2005 Elsevier Inc.保留所有权利。
Increased expression of vascular endothelial growth factor (VEGF) has been correlated with increased oxidative stress and formation of peroxynitrite in numerous disease conditions, including diabetic microangiopathy, tumor angiogenesis, and atherosclerosis. In this study we tested the hypothesis that peroxynitrite stimulates VEGF expression. Treatment of rnicrovascular endothelial cells with exogenous peroxynitrite induced a time- and dose-dependent increase in VEGF mRNA, which peaked within I h of treatment at a concentration of 100 mu M. The increase in VEGF mRNA was followed by a significant increase in VEGF protein. To define the molecular mechanisms involved, the effect of peroxynitrite was determined on the activation of two transcription factors known to regulate VEGF expression during hypoxia and tumor angiogenesis-signal transducer and activator of transcription 3 (STAT3) and hypoxia- inducible factor-1 (HIF-1). Peroxynitrite caused activation and nuclear translocation of STAT3, but not HIF-1. Moreover, transduction of endothelial cells with dominant-negative STAT3 abrogated the peroxynitrite-induced increase in VEGF mRNA. The increase in VEGF mRNA was also blocked by inhibitors of transcription and was unaffected by the inhibition of protein synthesis. These results indicate that peroxynitrite causes increased expression of VEGF in vascular endothelial cells by a process that requires the activation of STAT3. (c) 2005 Elsevier Inc. All rights reserved.