Figure 5. Activation of hypoxia-inducible factor (HIF)-dependent gene expression via prolyl hydroxylase inhibition.

Under hypoxic conditions (blue arrows), HIF-α and the constitutively expressed HIF-β bind and translocate into the cell nucleus. After binding to the DNA hypoxia response promoter element, the HIF heterodimer induces expression of hypoxia-sensitive genes. Under normoxic conditions (red arrows), prolyl hydroxylases (PHDs) hydroxylate HIF-α and thereby mark it for proteasomal degradation, effectively inhibiting HIF-dependent gene expression. Prevention of proteasomal HIF-α degradation using prolyl hydroxylase inhibitors, e.g., FG-2216,¹⁴⁴ activates hypoxia-activated signaling pathways even under normoxic conditions.