Cigarette Smoke-induced Oxidative/Nitrosative Stress Impairs VEGF- and Fluid Shear Stress-Media Signaling in Endothelial Cells (Retracted article. See vol. 18, pg. 1535, 2013)
Cigarette Smoke-induced Oxidative/Nitrosative Stress Impairs VEGF- and Fluid Shear Stress-Media Signaling in Endothelial Cells (Retracted article. See vol. 18, pg. 1535, 2013)
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DOI：
10.1089/ars.2009.2874
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发表时间：
2010-06-01
影响因子：
6.6
通讯作者：
Rahman, Irfan
中科院分区：
文献类型：
--
作者：
Edirisinghe, Indika;Arunachalam, Gnanapragasam;Rahman, Irfan
VEGF受体2（VEGFR 2）是一种酪氨酸激酶受体，由VEGF和流体剪切应力（FSS）激活，其下游信号传导在调节内皮功能（如细胞迁移、内皮依赖性舒张和血管生成）中是重要的。已知香烟烟雾（CS）引起氧化/亚硝化应激，导致酪氨酸激酶受体的修饰和下游信号传导受损。我们假设CS诱导的氧化/亚硝化应激损害VEGF和FSS介导的VEGFR 2活化，导致内皮功能障碍。用不同浓度的香烟烟雾提取物（CSE）处理人肺微血管内皮细胞和人脐静脉内皮细胞，研究VEGF或FSS介导的VEGFR 2磷酸化及其下游信号通路与内皮功能的关系。CSE治疗损害VEGF和FSS介导的VEGFR 2磷酸化，导致Akt对内皮型一氧化氮合酶（eNOS）磷酸化的损害。CS衍生的活性氧/氮物质与VEGFR 2反应，使VEGFR 2对其下游信号传导无活性。用一氧化氮清除剂（PTIO）、活性氧清除剂（SOD与过氧化氢酶的组合）和N-乙酰基-L-半胱氨酸预处理显著减弱了CSE诱导的VEGF介导的Akt和eNOS磷酸化的损伤。这些研究结果表明，CSE诱导的氧化/亚硝化应激损害VEGF和FSS介导的内皮细胞功能，并在CS诱导的肺和心血管疾病与内皮功能障碍的发病机制中具有重要意义。抗氧化剂。氧化还原信号。12，1355-1369.
VEGF receptor 2 (VEGFR2), a tyrosine kinase receptor, is activated by VEGF and fluid shear stress (FSS), and its downstream signaling is important in the regulation of endothelial functions, such as cell migration, endothelium-dependent relaxation, and angiogenesis. Cigarette smoke (CS) is known to cause oxidative/nitrosative stress, leading to modifications of tyrosine kinase receptors and impaired downstream signaling. We hypothesized that CS-induced oxidative/nitrosative stress impairs VEGF-and FSS-mediated VEGFR2 activation, leading to endothelial dysfunction. Human lung microvascular endothelial cells and human umbilical vein endothelial cells were treated with different concentrations of cigarette smoke extract (CSE) to investigate the VEGF-or FSS-mediated VEGFR2 phosphorylation and its downstream signaling involved in endothelial function. CSE treatment impaired both VEGF-and FSS-mediated VEGFR2 phosphorylation, resulting in impaired endothelial nitric oxide synthase (eNOS) phosphorylation by Akt. CS-derived reactive oxygen/nitrogen species react with VEGFR2, rendering VEGFR2 inactive for its downstream signaling. Pretreatment with nitric oxide scavenger (PTIO), reactive oxygen species scavengers (combination of SOD with catalase), and N-acetyl-l-cysteine, significantly attenuated the CSE-induced impairment of VEGF-mediated Akt and eNOS phosphorylation. These findings suggest that CSE-induced oxidative/nitrosative stress impairs VEGF-and FSS-mediated endothelial cell function and has important implications in the pathogenesis of CS-induced pulmonary and cardiovascular diseases associated with endothelial dysfunction. Antioxid. Redox Signal. 12, 1355-1369.