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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.

Original publication

DOI

10.1161/CIRCRESAHA.117.305109

Type

Journal article

Journal

Circ Res

Publication Date

19/06/2015

Volume

117

Pages

65 - 79

Keywords

dioxygenases, hypoxia, hypoxia inducible factor, prolyl hydroxylases, Adaptation, Physiological, Altitude, Animals, Basic Helix-Loop-Helix Transcription Factors, Cardiovascular Diseases, Cardiovascular System, Cell Hypoxia, Heart, Heart Defects, Congenital, Humans, Hydroxylation, Hypertension, Pulmonary, Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit, Hypoxia-Inducible Factor-Proline Dioxygenases, Iron, Ischemic Preconditioning, Myocardial, Mice, Mixed Function Oxygenases, Oxygen, Polycythemia, Protein Isoforms, Protein Processing, Post-Translational, Repressor Proteins, Von Hippel-Lindau Tumor Suppressor Protein