A role for the aryl hydrocarbon receptor in regulation of ischemia-induced angiogenesis
A role for the aryl hydrocarbon receptor in regulation of ischemia-induced angiogenesis
复制标题
DOI：
10.1161/atvbaha.106.138701
复制
发表时间：
2007-06-01
影响因子：
8.7
通讯作者：
Murohara, Toyoaki
中科院分区：
文献类型：
--
作者：
Ichihara, Sahoko;Yamada, Yoshiji;Murohara, Toyoaki
目的-芳烃受体 (AHR) 是一种转录因子，在与烟草烟雾和环境中发现的多环和卤代芳香烃等配体相互作用后，通过 AHR 核转位子 (ARNT) 与 DNA 结合为异二聚体。我们利用缺血手术模型研究了AHR和缺氧信号通路在血管生成调节中的相互作用。方法和结果-在野生型和AHR缺失小鼠中通过股动脉闭塞诱导缺血。与野生型动物相比，AHR 缺失小鼠的缺血诱导的血管生成显着增强。在 AHR 缺失小鼠中，缺血诱导的缺氧诱导因子 1 α (HIF-1 α) 和 ARNT 以及这些转录因子的靶基因（例如血管内皮生长因子 (VEGF)）的表达上调也得到增强。此外，与野生型动物相比，AHR 缺失小鼠中的 HIF-1 α-ARNT 复合物的 DNA 结合活性以及 HIF-1 α 和 ARNT 与 VEGF 基因启动子的关联在更大程度上因缺血而增加。 结论：AHR 的消除导致了缺血诱导的血管生成的增强。这种效应可能部分归因于缺血诱导的 VEGF 表达的相关增强，而这又可能是由 HIF-1 α-ARNT 异二聚体的丰度和活性增加引起的。
Objective-The aryl hydrocarbon receptor (AHR) is a transcription factor that binds to DNA as a heterodimer with the AHR nuclear translocator (ARNT) after interaction with ligands such as polycyclic and halogenated aromatic hydrocarbons found in tobacco smoke and the environment. We have investigated the interaction between AHR and hypoxia signaling pathways in regulation of angiogenesis with the use of a surgical model of ischemia.Methods and Results-Ischemia was induced by femoral artery occlusion in wild-type and AHR-null mice. Ischemia-induced angiogenesis was markedly enhanced in AHR-null mice compared with that in wild-type animals. Ischemia-induced upregulation of the expression of hypoxia-inducible factor-1 alpha (HIF-1 alpha) and ARNT as well as that of target genes for these transcription factors, such as that for vascular endothelial growth factor (VEGF), were also enhanced in AHR-null mice. Furthermore, the DNA binding activity of the HIF-1 alpha-ARNT complex as well as the association of HIF-1 alpha and ARNT with the VEGF gene promoter were increased by ischemia to a greater extent in AHR-null mice than in wild-type animals.Conclusions-Ablation of AHR resulted in enhancement of ischemia-induced angiogenesis. This effect was likely attributable in part to the associated enhancement of ischemia-induced VEGF expression, which in turn may be caused by an increased abundance and activity of the HIF-1 alpha-ARNT heterodimer.