The involvement of phosphoinositid 3-kinase/Akt pathway in the activation of hypoxia-inducible factor-la in the developing rat brain after hypoxia-ischemia

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.