HIF-1 versus HIF-2--is one more important than the other?

Abstract

Hypoxia is a state where oxygen availability/delivery is below the level necessary to maintain physiological oxygen tension for a particular tissue. It is well-established that when tissue demand exceeds its oxygen supply, a cascade of intracellular events is activated, with the elevation of the expression of hypoxia-inducible factors (HIFs). As a consequence, the extensive transcriptional response regulating angiogenesis, glucose metabolism, cell growth, metastasis and others processes is induced. The discovery of differences between HIF isoforms has provided new insights into HIFs biology. Importantly, the opposite effects can be exerted by HIF-1 and HIF-2 on the regulation of angiogenic response. Although both isoforms may upregulate the expression of pro-angiogenic vascular endothelial growth factor (VEGF), HIF-1 diminished the expression of interleukin-8 (IL-8) by inhibition of the Nrf2 transcription factor whereas HIF-2 augmented expression of IL-8 in an Nrf2-independent way but via upregulation of SP-1 activity. Moreover, the opposite regulation of c-Myc transcription factor by both HIF isoforms may influence IL-8 regulation. Complexity of effects exerted by both HIF isoforms resulting from the cooperation with other transcription factors should be subjected to intensive investigation especially in the context of pro-and anti-angiogenic therapies.