Modulation of the Hypoxic Response.

Hypoxia stimulates a variety of adaptive responses, many mediated via the hypoxia inducible factors (HIF) family of transcriptional complexes. The balance of HIF-1, -2 and -3 controls a variety of genes, directly up-regulating transcription of genes involved in erythropoiesis, angiogenesis, vasomotor tone, metabolic pathways and processes related to cell multiplication and survival, and indirectly reducing the transcription of genes with other effects. HIF transcription factors are heterodimers consisting of an oxygen-regulated alpha chain bound to the constitutive aryl hydrocarbon receptor nuclear translocator. Under circumstances where oxygen is abundant the activity of the alpha chain is blocked by the actions of members of a family of oxygen-, iron- and oxoglutarate-dependent dioxygenase enzymes. Hydroxylation of two critical prolyl residues by the HIF prolyl hydroxylases (PHD1-3) leads to recognition by the von Hippel-Lindau E3 ubiquitin ligase complex, polyubiquitylation of the alpha chain and its consequent destruction by the proteasome. Hydroxylation of an asparaginyl residue by Factor Inhibiting HIF prevents any surviving HIF alpha chains from recruiting p300-CBP proteins, important for maximal transcriptional activation. Under conditions of acute hypoxia enzyme activity is suppressed, the HIF alpha chains are allowed to exist in their active form and target gene transcription is enhanced. In sustained hypoxia, adaptive responses mediated by the HIF pathway reduce oxygen demand and increase oxygen supply and thus ultimately down-regulate the pathway. However, a number of other processes also modulate HIF signalling and the balance between HIF-1 and HIF-2 actions. These include the generation of antisense HIF-1 and micro RNAs, up-regulation of HIF-3 alpha, antagonism of the HIF-p300 interaction by CITED2, increased PHD2 and PHD3 levels and effects on the pool of ankyrins within the cell which compete with HIF for the action of FIH. Additionally, effects on intermediary metabolism, reactive oxygen species, iron availability, nitric oxide levels and redox status within the cell may modulate HIF activity. Together, these effects lead to a reduction in the magnitude of the HIF response even if oxygenation is not restored and are predicted to alter the responsiveness of the system when oxygenation is restored.