Ablation of the Transcription Factor Nrf2 Promotes Ischemia-Induced Neovascularization by Enhancing the Inflammatory Response
Ablation of the Transcription Factor Nrf2 Promotes Ischemia-Induced Neovascularization by Enhancing the Inflammatory Response
复制标题
DOI：
10.1161/atvbaha.110.204123
复制
发表时间：
2010-08-01
影响因子：
8.7
通讯作者：
Ichihara, Gaku
中科院分区：
文献类型：
--
作者：
Ichihara, Sahoko;Yamada, Yoshiji;Ichihara, Gaku
目的探讨核因子-红细胞2相关因子2 （Nrf2）在小鼠缺血手术模型新生血管中的潜在作用。方法和结果：转录因子Nrf2通过增加基因的转录来防止氧化应激，包括一些含有抗氧化反应元件的抗氧化酶的转录。对Nrf2（-/-）缺失小鼠和野生型小鼠进行股动脉结扎诱导缺血。与野生型小鼠相比，Nrf2（-/-）小鼠缺血诱导的新生血管增强。与野生型小鼠相比，Nrf2（-/-）小鼠缺血后肢中血红素加氧酶1和硫氧还蛋白1靶基因的表达和总谷胱甘肽浓度均降低。Nrf2（-/-）小鼠缺血后肢炎症细胞的浸润和粘附分子mRNA的丰度均高于野生型小鼠。Nrf2（-/-）小鼠缺血后肢中单核细胞趋化蛋白-1、肿瘤坏死因子- α、环氧化酶2和血管生成因子的表达也高于野生型小鼠。结论：消融Nrf2可促进缺血诱导的新生血管形成。这种效应可能是由于内皮细胞中抗氧化防御受损和活性氧积累增加所致；因此，炎症反应增强。（中华动脉血管杂志，2010;30:1553-1561）
Objective-To investigate the potential role of nuclear factor-erythroid 2-related factor 2 (Nrf2) in neovascularization with a murine surgical model of ischemia.Methods and Results-The transcription factor Nrf2 protects against oxidative stress by increasing the transcription of genes, including those for several antioxidant enzymes that contain an antioxidant response element. Ischemia was induced by femoral artery ligation in Nrf2-deficient (Nrf2(-/-)) and wild-type mice. Ischemia-induced neovascularization was enhanced in Nrf2(-/-) mice compared with that in wild-type mice. The expression of Nrf2 target genes for heme oxygenase 1 and thioredoxin 1 and the concentration of total glutathione in the ischemic hindlimb were reduced for Nrf2(-/-) mice compared with wild-type mice. The infiltration of inflammatory cells and the abundance of adhesion molecule mRNA were greater in the ischemic hindlimb of Nrf2(-/-) mice than in wild-type mice. The expression of monocyte chemoattractant protein-1, tumor necrosis factor-alpha, cyclooxygenase 2, and angiogenic factors in the ischemic hindlimb was also greater for Nrf2(-/-) mice than for wild-type mice.Conclusion-The ablation of Nrf2 promoted ischemia-induced neovascularization. This effect likely resulted from impaired antioxidant defense and increased accumulation of reactive oxygen species in endothelial cells; consequently, there was an enhanced inflammatory response. (Arterioscler Thromb Vasc Biol. 2010;30:1553-1561.)