The human side of hypoxia-inducible factor

Abstract

When humans are exposed to hypoxia, systemic and intracellular changes operate together to minimise hypoxic injury and restore adequate oxygenation. Emerging evidence indicates that the hypoxia-inducible factor (HIF) family of transcription factors plays a central regulatory role in these homeostatic changes at both the systemic and cellular levels. HIF was discovered through its action as the transcriptional activator of erythropoietin, and has subsequently been found to control intracellular hypoxic responses throughout the body. HIF is primarily regulated by specific prolyl hydroxylase-domain enzymes (PHDs) that initiate its degradation via the von Hippel-Lindau tumour suppressor protein (VHL). The oxygen and iron dependency of PHD activity accounts for regulation of the pathway by both cellular oxygen and iron status. Recent studies conducted in patients with rare genetic diseases have begun to uncover the wider importance of the PHD-VHL-HIF axis in systems-level human biology. These studies indicate that, in addition to regulating erythropoiesis, the system plays an important role in cardiopulmonary regulation. This article reviews our current understanding of the importance of HIF in human systems-level physiology, and is modelled around the classic physiological response to high-altitude hypoxia.

Fig 1

Empirically-derived relationship between haemoglobin concentration (Hb) and arterial partial pressure of oxygen (Pao₂) in Andean men. From Villafuerte et al (2004) (used with permission). The average Hb of young high-altitude natives is represented by an empirical equation that expresses Hb as a function of Pao₂. This equation was derived using data collated from several studies, which investigated approximately 200 healthy men aged 18–45 years. Measurements were largely made in members of the native Quechua population at altitudes ranging from sea level to 4860 m, and Pao₂ was calculated from arterial haemoglobin oxygen saturation. Pao₂ is primarily determined by the altitude of residence, and for a given altitude, a Hb of more than two standard deviations above average is considered excessive (Villafuerte et al, 2004).

Fig 2

Schematic representation of the PHD-VHL-HIF axis. The hypoxia-inducible factor (HIF)-α subunit is synthesised continuously but is rapidly destroyed in the presence of oxygen and iron. Oxygen- and iron-dependent prolyl hydroxylase domain (PHD) enzymes hydroxylate specific proline residues in HIF-α, increasing its affinity for the von Hippel-Lindau tumour suppressor protein (VHL). The binding of VHL to hydroxylated HIF-α then targets HIF-α for destruction by a multiprotein ubiquitin ligase (denoted ‘ligase’) that mediates proteasomal degradation of HIF-α subunits. Another oxygen- and iron-dependent enzyme, factor inhibiting HIF (FIH), hydroxylates an asparagine residue in HIF-α, reducing its ability to activate transcription by inhibiting binding of the transcriptional coactivator complex p300/CBP. Under hypoxic conditions, the hydroxylation of HIF-α by PHDs and FIH is inhibited and proteasomal degradation is thus slowed. HIF-α rapidly accumulates and dimerises with HIF-β, which is expressed constitutively and is present in excess. The p300/CBP coactivator is recruited, and the DNA binding complex subsequently up-regulates hypoxia-responsive genes. OH denotes hydroxyl group.