title: HIF hydroxylase pathways in cardiovascular physiology and medicine.
abstract: Hypoxia inducible factors (HIFs) are α/β heterodimeric transcription factors that direct multiple cellular and systemic responses in response to changes in oxygen availability. The oxygen sensitive signal is generated by a series of iron and 2-oxoglutarate-dependent dioxygenases that catalyze post-translational hydroxylation of specific prolyl and asparaginyl residues in HIFα subunits and thereby promote their destruction and inactivation in the presence of oxygen. In hypoxia, these processes are suppressed allowing HIF to activate a massive transcriptional cascade. Elucidation of these pathways has opened several new fields of cardiovascular research. Here, we review the role of HIF hydroxylase pathways in cardiac development and in cardiovascular control. We also consider the current status, opportunities, and challenges of therapeutic modulation of HIF hydroxylases in the therapy of cardiovascular disease.
authors.affiliation: From the Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Tammie
authors.initials: T
authors.lastname: Bishop
authors.affiliation: From the Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. pjr@well.ox.ac.uk.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ratcliffe
mesh_terms: D000222:Adaptation, Physiological; D000531:Altitude; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D002319:Cardiovascular System / Q000201:enzymology / Q000378:metabolism*; D015687:Cell Hypoxia; D006321:Heart / Q000196:embryology; D006330:Heart Defects, Congenital / Q000196:embryology / Q000201:enzymology; D006801:Humans; D006900:Hydroxylation; D006976:Hypertension, Pulmonary / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007501:Iron / Q000502:physiology; D019157:Ischemic Preconditioning, Myocardial; D051379:Mice; D006899:Mixed Function Oxygenases / Q000502:physiology; D010100:Oxygen / Q000378:metabolism; D011086:Polycythemia / Q000201:enzymology / Q000235:genetics; D020033:Protein Isoforms; D011499:Protein Processing, Post-Translational; D012097:Repressor Proteins / Q000502:physiology; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D007501:Iron; D006899:Mixed Function Oxygenases; D010100:Oxygen; D020033:Protein Isoforms; D012097:Repressor Proteins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C439790:HIF1AN protein, human; C490190:EGLN1 protein, human
keywords: dioxygenases; hypoxia; hypoxia inducible factor; prolyl hydroxylases