Regulation of hypoxia-inducible factor (HIF)-1 activity and expression of HIF hydroxylases in response to insulin-like growth factor I

Hypoxia-inducible factor-1 (HIF-1), a transcription factor composed of two subunits (HIF-1 alpha and HIF-1 beta), initially described as a mediator of adaptive responses to changes in tissue oxygenation, has been shown to be activated in an oxygen-independent manner. In this report, we studied the action of IGF-I on the regulation of HIF-1 in human retinal epithelial cells. We show that IGF-I stimulates HIF-1 alpha accumulation, HIF-1 alpha nuclear translocation, and HIF-1 activity by regulation of HIF-1 alpha expression through a posttranscriptional mechanism. In addition, we demonstrate that IGF-I stimulates HIF-1 activity through phosphatidylinositol-3- kinase/mammalian target of rapamycin and MAPK-dependent signaling pathways leading to VEGF ( vascular endothelial growth factor) mRNA expression. Three human prolyl-hydroxylases PHD-1, -2, and -3 (PHD-containing protein) and an asparaginyl-hydroxylase factor inhibiting HIF-1, which regulate HIF-1 alpha stability and HIF-1 activity in response to hypoxia, have been described. Our analysis of their mRNA expression showed a different magnitude and time course of expression pattern in response to insulin and IGF-I compared with CoCl2. Taken together, our data reveal that growth factors and CoCl2, which mimics hypoxia, lead to HIF-1 activation and ensuing VEGF expression by different mechanisms. Their joined actions are likely to lead to an important and sustained increase in VEGF action on retinal blood vessels, and hence to have devastating effects on the development of diabetic retinopathy.