Department of Human Functional Genomics, Life Science Research Center, Mie University, 1577 Kurimamachiya-cho, Tsu 514-8507, Japan.
Arterioscler Thromb Vasc Biol. 2010 Aug;30(8):1553-61. doi: 10.1161/ATVBAHA.110.204123. Epub 2010 May 6.
To investigate the potential role of nuclear factor-erythroid 2-related factor 2 (Nrf2) in neovascularization with a murine surgical model of ischemia.
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.
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.
利用缺血性手术模型研究核因子-红细胞 2 相关因子 2（Nrf2）在血管新生中的潜在作用。
转录因子 Nrf2 通过增加抗氧化基因的转录来保护细胞免受氧化应激，这些基因包括几种抗氧化酶，它们包含抗氧化反应元件。通过股动脉结扎在 Nrf2 缺陷（Nrf2(-/-)）和野生型小鼠中诱导缺血。与野生型小鼠相比，Nrf2(-/-)小鼠的缺血诱导血管新生增强。与野生型小鼠相比，Nrf2(-/-)小鼠缺血后肢的血红素加氧酶 1 和硫氧还蛋白 1 的 Nrf2 靶基因表达和总谷胱甘肽浓度降低。Nrf2(-/-)小鼠缺血后肢的炎症细胞浸润和粘附分子 mRNA 丰度大于野生型小鼠。Nrf2(-/-)小鼠缺血后肢的单核细胞趋化蛋白-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。
Nrf2 的缺失促进了缺血诱导的血管新生。这种作用可能是由于内皮细胞抗氧化防御受损和活性氧的积累增加，从而导致炎症反应增强。
