Figure 1

A schematic display of hypoxia-inducible factor (HIF) regulation and biological action. Prolyl-4 hydroxylases (PHDs) serve as oxygen sensors and under normoxic conditions promote degradation of HIF-α isoforms in the proteasome following binding with the ubiquitin ligase, Von-Hippel-Lindau protein (VHL). Hypoxia inhibits PHDs and leads to HIF-α accumulation with HIF-β, and the αβ heterodimer translocates into the nucleus, binds with hypoxia-response elements (HRE) and activates numerous genes important in cell metabolism, proliferation and survival. Many of these genes play a central role in injury tolerance and promotion of tissue oxygenation, such as erythropoietin (EPO), vascular endothelial growth factor (VEGF), inducible NO synthase (iNOS), heme oxygenase (HO)-1, glucose transporter-1, or carbonic anhydrase (CA)-9. Underscored is the inactivation of the HIF-HRE axis by hypoxia, which can be mimicked by carbon monoxide (functional anemia) or by transition metals like cobaltous chloride. Hypoxia-mimetic PHD inhibitors (PHD-I) are potent newly developed measures in the induction of the HIF-HRE axis. For simplicity, numerous additional factors involved in HIF regulation and action are not included in this cartoon and the reader is referred to comprehensive reviews such as references [3, 12].