The involvement of phosphoinositid 3-kinase/Akt pathway in the activation of hypoxia-inducible factor-la in the developing rat brain after hypoxia-ischemia
The involvement of phosphoinositid 3-kinase/Akt pathway in the activation of hypoxia-inducible factor-la in the developing rat brain after hypoxia-ischemia
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DOI：
10.1016/j.brainres.2007.12.059
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发表时间：
2008-03-04
期刊：
影响因子：
2.9
通讯作者：
Mu, Dezhi
中科院分区：
文献类型：
--
作者：
Li, Lihua;Qu, Yi;Mu, Dezhi
低氧诱导转录因子(HIF)-1α在维持氧稳态中起重要作用。然而，参与HIF-1α调控的途径尚不清楚。由于磷酸肌醇3-激酶/Akt(PI3K/Akt)通路是参与细胞信号转导的常见途径，因此我们推测PI3K/Akt通路参与了发育中大鼠脑缺氧缺血后HIF-1α的调节。为了验证这一假设，我们对出生后第10天的大鼠进行了HI，方法是结扎颈总动脉，然后进行缺氧。免疫组织化学和Western印迹分析检测HIF-1α及其靶基因血管内皮生长因子(VEGF)和PI3K/Akt的表达。我们发现HIF-1α的表达。与假手术对照组相比，血管内皮细胞生长因子在缺氧缺血后8h显著上调并达到高峰。而p-Akt的表达高峰在4h，早于HIF-1α的表达。此外，我们还发现，用一种特异性的抑制剂wortmannin阻断PI3K/Akt通路后，HIF-1α和VEGF蛋白的表达明显受到抑制。我们的研究结果提示，PI3K/Akt通路参与了HIF-1α及其靶基因血管内皮生长因子在脑缺血后发育过程中的调控。(C)2007 Elsevier B.V.保留所有权利。
Hypoxia inducible transcription factor (HIF)-1 alpha plays an important role in maintaining oxygen homeostasis. However, the pathways involved in the regulation of HIF-1 alpha are not clear. Since phosphoinositid 3-kinase/Akt (PI3K/Akt) pathway has been shown to be a common pathway involved in cell signaling, we therefore hypothesized that PI3K/Akt pathway is involved in the regulation of HIF-1 alpha in developing rat brain after hypoxia-ischemia (HI). To test this hypothesis, we subjected postnatal day 10 rats to HI by ligating common carotid artery followed by hypoxia. Rat brains were collected to detect the expression of HIF-1 alpha and its target gene, vascular endothelial growth factor (VEGF), as well as PI3K/Akt using immunohistochemistry and Western blot analysis. We found that the expression of HIF-1 alpha. and VEGF was significantly upregulated and peaked at 8 h after HI compared with sham controls. However, the expression of p-Akt peaked at 4 h, earlier than that seen in HIF-1 alpha expression. Furthermore, we found that HIF-1 alpha and VEGF protein were significantly inhibited after blocking the PI3K/Akt pathway using a specific inhibitor, wortmannin. Our findings suggest that the PI3K/Akt pathway is involved in the regulation of HIF-1 alpha and its target gene VEGF in the developing rat brain after HI. (C) 2007 Elsevier B.V. All rights reserved.