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.

Keywords: dioxygenases; hypoxia; hypoxia inducible factor; prolyl hydroxylases.

Figure 1. Oxygen-dependent regulation of HIFalpha by prolyl and asparaginyl hydroxylation

In the presence of oxygen, both HIF prolyl hydroxylases (PHDs) and factor inhibiting HIF (FIH) are active. PHDs hydroxylate two proline residues on HIFalpha, targeting HIFalpha for VHL-mediated proteasomal degradation. Under hypoxia, PHDs are inactive and HIFalpha escapes proteolytic degradation. FIH hydroxylates one asparaginyl residue on HIFalpha to prevent binding of the transcriptional coactivator p300/CBP, thus reducing the transcriptional potential of HIF. Under more severe hypoxia, FIH is also inactivated, allowing for p300/CBP binding to HIFalpha and resulting in transcriptional activation. CITED2, a HIF target gene, acts as a negative regulator of HIF activation by competing with HIFalpha for binding to p300/CBP.

Figure 2. HIF and cardiovascular development

The developing heart is hypoxic in a spatiotemporal-restricted manner. Physiological hypoxia activates HIFalpha and HIF dependent processes (such as cardiac transcription factors, TFs) which interface with developmental pathways to direct cardiogenesis. Disturbances to these spatiotemporal variations in hypoxia (for example through maternal systemic hypoxia or insufficient feto-placental oxygen delivery) alter HIF expression. This may interfere with cardiac development either directly by disturbing activation of HIF dependent processes and/or indirectly by disturbing placentation and therefore feto-placental oxygen delivery to exacerbate hypoxia.

Figure 3. Therapeutic modulation of HIF

Activation of HIF in the heart, either before or after myocardial ischaemia (MI), confers ischaemia protection (known as pre-conditioning or postconditioning, respectively). However, if HIF activation is either prolonged in duration and/or excessive in its level (pink arrows), then it may result in contractile impairment and cardiomyopathy. This suggests a temporal and dose-related therapeutic window for optimal effects of HIF activation on cardiac function.