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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

Circulation research

Publication Date

06/2015

Volume

117

Pages

65 - 79

Addresses

From the Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.

Keywords

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