Hypoxia-induced mediators and neurologic disease

ALS= : amyotrophic lateral sclerosis; AMPA= : α-amino-3-hydroxy-5-methyl-4-isoxazole propionate; ATP= : adenosine triphosphate; CBP= : CREB-binding protein; COX= : cytochrome c oxidase; CREB= : cAMP-response-element-binding protein; EPO= : erythropoietin; EPOR= : EPO receptor; FIH= : factor inhibiting HIF; GLUT-1= : glucose transporter-1; HIF= : hypoxia-induced factor; HRE= : hypoxia-regulated element; IDH= : isocitrate dehydrogenase; NADPH= : nicotine-adenine nucleotide phosphate; NFκB= : nuclear factor kappa B; NOS= : nitric oxide synthase; NP= : neuropilin; PHD= : prolyl hydroxylase domain enzyme; PI3K/Akt= : phosphatidylinositol 3′kinase-Akt; POEMS= : polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes; ROS= : reactive oxygen species; Ub= : ubiquitin; VEGF= : vascular endothelial growth factor; VEGFR= : VEGF receptor; VHL= : von Hippel–Lindau. Oxygen is the final electron acceptor in the aerobic metabolism of glucose that generates adenosine triphosphate (ATP), the source of energy for most active cellular processes. Cells have a rapid and efficient molecular response system that senses hypoxia and triggers an evolutionarily conserved pathway mediated by hypoxia-induced factor (HIF). This transcriptional regulator promotes induction of several adaptive genes that facilitate oxygen supply and support anaerobic ATP production. These genes include those encoding for glucose transporter-1 (GLUT-1), glycolytic enzymes, vascular endothelial growth factor (VEGF), and erythropoietin (EPO). During normoxia, the product of the von Hippel–Lindau (VHL) tumor suppressor gene binds to HIF and triggers its ubiquitin-mediated proteolysis. Whereas the hypoxia response has a critical adaptive role in normal cell functioning, its multiple effectors have also been implicated either in the pathogenesis or as neuroprotective factors in several neurologic disorders, including hemangioblastoma, malignant glioma, and cerebral ischemia. Both the VEGF and EPO signaling pathways are potential therapeutic targets in these and other conditions. There are several excellent reviews on all these topics.1–15 ### Hypoxia-inducible factor and oxygen sensing. HIFs are transcription factors that bind to canonical DNA sequences called hypoxia-regulated elements. These factors activate the expression of many genes encoding proteins that regulate cell metabolism, angiogenesis, vascular tone, erythropoiesis, and other functions.1–3 HIF is a heterodimeric DNA-binding complex composed of one hypoxia-inducible HIFα-subunit (HIF1α or HIF2α) and a constitutive non-oxygen-responsive subunit HIF1β.1–3 The HIF pathway is regulated by oxygen-dependent posttranslational hydroxylation of HIFα, which results in its rapid inactivation and degradation during normoxia (figure 1). HIFα subunits are substrates of a family of oxygen-dependent enzymes, including prolyl hydroxylase domain enzymes (PHDs) and aspargyl hydroxylase (factor inhibiting HIF, FIH). These enzymes act as oxygen sensors and catalyze the hydroxylation of HIFα at specific residues during normoxic conditions.1–4 These hydroxylases utilize molecular oxygen and require ferrous …