Nox1 transactivation of epidermal growth factor receptor promotes N-cadherin shedding and smooth muscle cell migration
Nox1 transactivation of epidermal growth factor receptor promotes N-cadherin shedding and smooth muscle cell migration
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DOI：
10.1093/cvr/cvr308
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发表时间：
2012-03-01
影响因子：
10.8
通讯作者：
Miller, Francis J., Jr.
中科院分区：
文献类型：
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作者：
Jagadeesha, Dammanahalli K.;Takapoo, Maysam;Miller, Francis J., Jr.
在动脉粥样硬化和再狭窄中，血管平滑肌细胞（SMC）迁移到内皮下空间并增殖，促进新生内膜形成。本研究的目的是确定Nox 1 NAPDH氧化酶介导SMC迁移的信号通路。SMC培养自Nox 1（/y）（Nox 1敲除，KO）和野生型（WT）小鼠的胸主动脉。响应凝血酶，WT而不是Nox 1 KO SMC产生的活性氧（ROS）水平增加。Nox 1的缺乏阻止凝血酶诱导的Src磷酸化和随后的表皮生长因子受体（EGFR）在多个酪氨酸残基的反式激活。接下来，凝血酶对细胞外信号调节激酶1/2（ERK 1/2）和基质金属蛋白酶-9（MMP-9）的激活被EGFR抑制剂AG 1478和Nox 1 KO SMC抑制。凝血酶诱导的N-钙粘蛋白从质膜脱落依赖于Nox 1的存在，并被AG 1478和金属蛋白酶抑制剂阻断。平滑肌细胞向凝血酶的迁移在Nox 1 KO平滑肌细胞中受损，并通过Nox 1的表达恢复。最后，用AG 1478处理WT SMC废除了Nox 1依赖的SMC迁移，Nox 1 NADPH氧化酶通过EGFR信号激活MMP-9并促进N-cadherin脱落，从而促进SMC迁移。
In atherosclerosis and restenosis, vascular smooth muscle cells (SMCs) migrate into the subendothelial space and proliferate, contributing to neointimal formation. The goal of this study was to define the signalling pathway by which Nox1 NAPDH oxidase mediates SMC migration.SMCs were cultured from thoracic aorta from Nox1(/y) (Nox1 knockout, KO) and wild-type (WT) mice. In response to thrombin, WT but not Nox1 KO SMCs generated increased levels of reactive oxygen species (ROS). Deficiency of Nox1 prevented thrombin-induced phosphorylation of Src and the subsequent transactivation of the epidermal growth factor receptor (EGFR) at multiple tyrosine residues. Next, activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and matrix metalloproteinase-9 (MMP-9) by thrombin was inhibited by the EGFR inhibitor AG1478 and in Nox1 KO SMCs. Thrombin-induced shedding of N-cadherin from the plasma membrane was dependent on the presence of Nox1 and was blocked by AG1478 and an inhibitor of metalloproteinases. Migration of SMCs to thrombin was impaired in the Nox1 KO SMCs and was restored by expression of Nox1. Finally, treatment of WT SMCs with AG1478 abrogated Nox1-dependent SMC migration.The Nox1 NADPH oxidase signals through EGFR to activate MMP-9 and promote the shedding of N-cadherin, thereby contributing to SMC migration.