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Hot Topic Review |
1 Hammersmith Campus, Imperial College, Du Cane Road, London W12 0NN, UK
Abstract
Hypoxia-inducible factor (HIF) is a transcription complex which responds to changes in oxygen, providing cells with a master regulator that coordinates changes in gene transcription. HIF operates in all mammalian cell types and is ancient in evolutionary terms, being conserved in C. elegans and D. melanogaster. This review summarizes recent insights into the molecular events that link reduced oxygenation to HIF activation and emerging insights into the extensive role of HIF in a broad range of physiological processes.
(Received 8 August 2005;
accepted after revision 7 September 2005; first published online 12 September 2005)
Corresponding author P. H. Maxwell: Hammersmith Campus, Imperial College, Du Cane Road, London W12 0NN, UK. Email: p.maxwell{at}imperial.ac.uk
Hypoxia-inducible factor (HIF) was identified from its role in regulating transcription of the erythropoietin (EPO) gene (Wang et al. 1995). EPO is a circulating hormone, mainly produced by the kidney, which is required for red blood cell production by the bone marrow. This system provides a striking example of physiological homeostasis. If blood oxygen content falls, for example in anaemia or at altitude, HIF is activated in renal fibroblasts and erythropoietin production is rapidly increased, which drives an adaptive increase in red cell production. It is now clear that HIF regulates many other genes besides erythropoietin (Wiesener & Maxwell, 2003).
Recently we have learned a great deal about how this system works at a molecular level. Understanding of the physiological roles of this pathway has lagged behind. Given the fundamental requirement of cells for oxygen, it is not very surprising that the HIF system is implicated in many aspects of development, physiology and disease. As might be anticipated for such a potentially important cellular pathway, knockouts of individual components have drastic effects. More subtle approaches, including analyses of transgenic mice which are heterozygous for a defect in the HIF 
subunit, development of tissue-specific knockouts and identification of humans with perturbations in the system, are now providing some fascinating insights.
Composition of the HIF complex
At a molecular level, an HIF complex contains an and a ß subunit, both of which can be selected from several alternatives. They are members of a large family of transcription factors which contain a basic helix–loop–helix region and a PAS domain (named for Per, Arnt/HIF-1ß and Sim). HIF ß subunits are constitutive and are also involved in xenobiotic responses. The subunit is regulatory and is unique to the hypoxic response. Three different genes encoding HIF subunits are found in mammals: HIF-1, HIF-2 and HIF-3/IPAS (IPAS is inhibitory PAS protein). As yet, the role(s) of HIF-3 are unclear, but are likely to be complex since the gene produces six different transcripts, some of which encode proteins which are predicted to be oxygen responsive while others are not.
Transcriptional targets of HIF
The HIF system operates on many genes besides EPO. The downstream consequences of HIF activation vary significantly from one cell type to another, which is unsurprising given that different cells and organs in vivo need to make different adaptations in the face of changes in oxygen supply. Currently there are of the order of a hundred genes that are recognized transcriptional targets of HIF. Besides erythropoiesis, the best-characterized processes that are regulated by HIF are angiogenesis, and glucose uptake and metabolism. In both cases, the homeostatic nature of the response is clear. The increased glucose uptake and expression of glycolytic enzymes increases the ability of cells to generate ATP by glycolysis, which can then compensate for impaired mitochondrial electron transport. The increase in angiogenic signalling promotes an increase in the vascular supply. Many of the other targets of HIF could be regarded as adaptive. Some interesting examples are the surface membrane carbonic anhydrases, CA IX and CA XII. These HIF targets are presumed to be important in compensating for local increases in hydrogen ion generation. Another intriguing recent discovery is that the CXC motif chemokine receptor, CXCR4, and its ligand, stromal cell-derived factor-1, are both HIF targets. This provides a means by which circulating multipotent stem cells could be guided to niches where repair is required in response to injury (Ceradini et al. 2004). Interestingly, many enzymes that use molecular oxygen as cosubstrates are HIF targets, perhaps because increased expression provides an effective way for maintaining reaction rate at lower concentrations of oxygen. Not surprisingly, HIF activation is also important in decisions concerning cellular proliferation and apoptosis. Of interest to physiologists, there are several examples of ion channels, transporters, circulating hormones and receptors that are modulated by HIF.
Little is known about what shapes the downstream consequences of HIF activation, but it presumably involves the range of genes in particular cells that is available for transcription, and complex interactions with other transcriptional control mechanisms. It is clear that HIF-1 and HIF-2 can operate selectively on downstream targets, although the way in which this is achieved is not yet understood (Warnecke et al. 2004; Raval et al. 2005). Illustrating the potential complexity, the extent of functional overlap between HIF-1 and HIF-2 appears to be different from one cell type to another.
From a physiological perspective, the important message is that HIF activation is capable of mediating a response that is precisely tailored to the requirements of the cell, tissue and organism. The range of downstream responses is very broad indeed and could include almost any pathway. Overall this might seem rather daunting. However, we now have a very comprehensive range of molecular, cellular and genetic tools. Taken together with the relative ease with which oxygen delivery can be altered in vivo and in vitro, this has allowed precise insights concerning the role of HIF in particular processes.
Mechanism of regulation of HIF by oxygen
When oxygen levels fall, HIF is activated (Fig. 1). This regulation mainly involves post-transcriptional changes in the stability and transcriptional activity of HIF-1/HIF-2. The interface with oxygen is provided by enzymatic hydroxylation of conserved asparaginyl and prolyl residues (Schofield & Ratcliffe, 2004). The reactions require molecular oxygen as a cosubstrate, and the reaction rate responds directly to the concentration of oxygen. The enzymes carrying out these hydroxylation reactions are members of an extended family of 2-oxoglutarate-dependent dioxygenases. The family is characterized by a ß-barrel jelly roll fold, with a ferrous ion co-ordinated at the active site.
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/HIF-2 efficiently interacts with the CH1 pocket of the transcriptional coactivator CBP/P300. In the presence of oxygen, the HIF asparaginyl hydroxylase FIH adds an atom of oxygen to the ß-carbon of Asn803 (the numbering given is for human HIF-1). This modification prevents the recruitment of CBP/P300. HIF stability is controlled by prolyl hydroxylation. In the presence of oxygen, HIF prolyl hydroxylases add an atom of oxygen to Pro403 and/or Pro564, converting the residue to 4-hydroxyproline. This provides the recognition signal for capture by a specific ubiquitin E3 ligase complex. The interaction with HIF- is mediated by the von Hippel–Lindau (VHL) protein, which has a surface pocket into which the hydroxyproline residue fits accurately. The multiprotein E3 ligase complexed with VHL leads to polyubiquitylation of the HIF subunit, which is then destroyed by the proteasome. Three different HIF prolyl hydroxylases have been identified: PHD1 (standing for prolyl hydroxylase domain 1; also known as Falkor or EglN3), PHD2 (C1ORF12 or EglN1) and PHD3 (SM-20 or EglN3). As yet, the extent to which these enzymes are redundant is unclear. RNA interference (knockdown) studies have established that a decrease in PHD2 activity is sufficient to activate HIF in most cells under standard conditions (Berra et al. 2003; Appelhoff et al. 2004). Additionally, a biochemical approach to purification of HIF prolyl hydroxylase activity from reticulocyte lysate led to the isolation of PHD2 (Ivan et al. 2002). The present evidence therefore suggests that PHD2 is the predominant HIF hydroxylase in most cells under normal circumstances. However, at least in cultured cells, it is clear that there is considerable ability to vary the expression of the PHD enzymes. When PHD1 or PHD3 is expressed at a higher level, either artificially, or in response to hormonal stimulation (PHD1) or prolonged hypoxia (PHD3), then they are functionally important in hydroxylating HIF (Appelhoff et al. 2004). So far, no substrates of the PHD or FIH enzymes besides HIF- subunits have been securely identified. Implications of understanding the oxygen-sensing mechanism
An important aspect of the molecular basis of oxygen sensitivity that underlies the HIF response is the extent to which it explains the ability of some agents to activate HIF. For example, cobalt(II) ions and iron chelators both induce HIF, which can now be explained on the basis that substitution of the ferrous ion, or its removal from the active site of the PHD and FIH enzymes, prevents enzyme activity. The underlying mechanism also allowed various important predictions concerning adjustment of the basic HIF response. First, since the reactions are not at equilibrium, it would be predicted that increasing the level of expression of the enzymes would increase the reaction rate, potentially ameliorating the response to moderate hypoxia. Second, the level of tricarboxylic acid cycle intermediates in the cell might alter enzyme activity. This has recently been confirmed; increasing levels of succinate or fumarate, either pharmacologically, or through genetic decreases in succinate dehydrogenase or fumarate hydratase, can induce HIF by decreasing hydroxylase activity (Isaacs et al. 2005; Selak et al. 2005). Third, the level of available intracellular iron may be important in modulating HIF activity. In fact, under some circumstances this may act primarily as an iron-response rather than oxygen-response system. Fourth, it suggested that ascorbate might influence enzyme activity, either because the enzymes might require ascorbate for full in vivo activity, or because of effects on intracellular iron availability. This is based on the fact that the related enzyme, procollagen prolyl-4-hydroxylase, requires ascorbate. Recent experimental evidence shows that ascorbate supplementation decreases HIF activation in some cultured cells, confirming that this can be biologically important (Knowles et al. 2003).
Perhaps the most important implication of understanding the molecular oxygen-sensing mechanism is that it offers a relatively simple route to designing small molecules that would activate HIF, either by inhibiting VHL-mediated capture, or by inhibiting HIF hydroxylation. One set of situations in which this might be attractive would be to protect tissues such as heart, brain or kidney from ischaemia. Another possible therapeutic application would be to promote production of erythropoietin, for example in the anaemia seen in chronic kidney disease.
The role of HIF in normal physiology and pathological processes
The potential for HIF to regulate physiological responses in mammals is clear. Tissue oxygenation is variable, and HIF regulates expression of many different genes. In addition, changing oxygen delivery produces extensively documented alterations in many physiological parameters. However, precise knowledge of the extent of the role of HIF in physiological and pathological processes is still in its infancy. One way of gaining insight into this has been to use immunodetection of HIF- subunits. Since HIF is largely regulated by destruction of the subunits, their presence provides a good indicator of activation, especially when combined with increased expression of known HIF target genes. Important conclusions from this approach include: (a) under baseline conditions, normal tissues show little evidence of HIF activation (Stroka et al. 2001); (b) HIF can be activated by reducing oxygen delivery; (c) HIF-1 and HIF-2 are commonly activated in different cell populations (Rosenberger et al. 2002; Wiesener et al. 2003); and (d) HIF is often activated in solid tumours (Zhong et al. 1999; Talks et al. 2000).
An important recent development is the identification of humans with genetic variation in the HIF system, and the creation of mice with alterations in the HIF pathway. These developments offer the ability to obtain precise answers to questions concerning the role of HIF in different settings.
Variation in the HIF pathway in humans
Appreciation of genetic variations in the HIF system in humans is increasing. Best characterized are individuals with von Hippel–Lindau disease, caused by a germline mutation in the VHL gene. Affected families are at risk for renal cell carcinoma (
70% risk over a lifetime), haemangioblastomas of the retina and central nervous system, and pheochromocytoma (a tumour of the adrenal gland), together with less serious clinical manifestations. All of these are associated with somatic inactivation of the normal VHL allele, explaining the variable clinical penetrance. Although von Hippel–Lindau disease is rare, it has given insight into the commonest type of kidney cancer because the great majority of cases show biallelic VHL inactivation due to two independent somatic hits. In VHL patients in the absence of this second hit, there is not an obvious cellular phenotype, implying that any effects of haploinsufficiency of VHL are limited. Interestingly, there does appear to be altered apoptosis of neutrophils in hypoxia, suggesting that there are likely to be more subtle phenotypic effects; potentially this would offer a very powerful method of determining the effect of rather minor changes in HIF in normal physiology (Walmsley et al. 2005). In VHL disease, the haemangioblastoma and clear cell renal cell carcinoma are both associated with constitutive HIF activation, which accounts for many of the features of these tumours, including marked angiogenesis. Current evidence suggests that HIF activation occurs immediately on inactivation of the second VHL allele, but has relatively little effect on the balance between cell proliferation and death (Mandriota et al. 2002). Normal renal epithelium that is hypoxic or in which VHL is inactivated expresses HIF-1, with little or no HIF-2. Evolution to cancer seems to involve a progressive switch to increased levels of HIF-2, which is critical for tumour growth, at least in xenograft experiments (Kondo et al. 2003; Raval et al. 2005). Interestingly, it is likely that pheochromocytoma involves a VHL-dependent pathway other than HIF (Clifford et al. 2001; Hoffman et al. 2001).
Recently, investigation of familial erythrocytosis (excess red blood cell production) showed that this can be caused by homozygosity for a hypomorphic VHL allele (Ang et al. 2002). This shows that altered VHL function is sufficient to dysregulate erythropoiesis in humans, presumably by generating an inappropriate signal in the fibroblasts in the kidney. Importantly, these individuals have a minor defect in HIF regulation in all cells, rather than the major defect in some cells that is seen in classical VHL disease. They therefore offer a powerful resource for asking whether partial genetic activation of HIF in humans has physiological consequences. Our preliminary observations suggest that they have increased respiratory sensitivity to hypoxia, and also an increased pulmonary vascular response.
Another approach has been to correlate more common genetic variants in the HIF system with phenotypes. Studies to date suggest that polymorphisms resulting in increased HIF activity may be associated with predisposition to cancer and also with type II diabetes (Tanimoto et al. 2003; Yamada et al. 2005). Replication of the disease associations in other populations will be of importance, since it is well recognized that population stratification can generate false positive findings in this type of study. Another interesting approach has been to examine the hypoxic response of cultured monocytes (assessed by ex vivo vascular endothelial growth factor (VEGF) expression) with in vivo parameters, such as the presence of proliferative retinopathy in diabetics, or the degree of collateral formation in patients with ischaemic heart disease (Schultz et al. 1999; Marsh et al. 2000). The results show that there is marked variation in ex vivo hypoxic responses and strongly suggest that this plays an important part in determining the outcomes in ischaemia.
Modifying the HIF pathway in mice
Modifications to the HIF pathway in mice have underlined its importance in development. Embryos with inactivating mutations in HIF-1, HIF-2 and HIF-1ß all die in mid or late gestation. In the case of HIF-2 the severity of the phenotype and timing of lethality has been more variable, and some interesting physiological findings have emerged. First, it is clear that redundancy between HIF-1 and HIF-2 is limited. Second, HIF-2 has a more specialized role, being important in yolk sac vascularization, development and function of the autonomic nervous system, and surfactant formation in the lung at birth (Tian et al. 1998; Peng et al. 2000; Compernolle et al. 2002). Third, by selective breeding, viable adult animals lacking HIF-2 were obtained. These have a defect in haemopoiesis and a striking metabolic phenotype (Scortegagna et al. 2003a,b). Embryos with inactivation of VHL (Gnarra et al. 1997), which will result in HIF activation, are also not viable. In this case, the defect is in placental development, demonstrating that normal function of this system is essential for development of an appropriate interface between the maternal and fetal circulations.
In general, these drastic modifications have given rather limited physiological insights. Recently, much more information has come from two new approaches: analysis of mice with heterozygous defects in HIF- subunits, and the use of Cre recombinase-lox P technology to effect manipulations in specific cell populations. Mice with heterozygous defects in HIF-1a show decreased carotid body responses to hypoxia, resistance to developing pulmonary hypertension in hypoxia, and a diminished protective effect of hypoxic preconditioning in a model of cardiac ischaemia (Yu et al. 1999; Kline et al. 2002; Cai et al. 2003). Mice with partial defects in HIF-2 also show protection from pulmonary hypertension in hypoxia (Brusselmans et al. 2003), suggesting that both HIF-1 and HIF-2 are involved in pulmonary vascular responses.
A number of elegant experiments have now been performed to examine the consequences of tissue-specific loss of function of HIF-1. These are summarized in Table 1, and show that the VHL/HIF-1 system is critical for normal function of many cell types. A particular strength of this system has been the ability to show that defects in VHL and HIF have opposite effects, and that combining them leads to a relatively normal phenotype. Findings of particular interest to physiologists may be that HIF-1 (a) is critical for myeloid cells to execute an inflammatory response; (b) may be harmful in acute cerebral ischaemia; and (c) has important effects on skeletal and cardiac muscle metabolism.
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The HIF system provides a molecular basis for understanding a set of classical physiological responses. Extensive observations concerning erythropoiesis in humans and experimental animals were critical in uncovering how this molecular oxygen response system works. An exciting recent development is the reverse process, i.e. using genetic approaches to determine how extensively this ancient oxygen response system is used in normal physiology. It is increasingly evident that it shapes very extensive aspects of development, physiology and disease. An exciting aspect of this is that our understanding of the underlying molecular biology and biochemistry allows very accurate answers to be obtained, and the possibility of selective therapeutic manipulation.
An important challenge is to understand the scope of the role of HIF in physiology. A parallel endeavour is to solve another longstanding puzzle, the molecular mechanism(s) by which glomus cells in the carotid body depolarize in response to hypoxia (Lopez-Barneo et al. 2004). Like HIF, aspects of the underlying system are expected to be used widely in physiology, since many different ion channels are oxygen responsive.
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Acknowledgements
Work in the author's laboratory is funded by the British Heart Foundation, the Wellcome Trust, the Medical Research Council, the EU FP6 Integrated Project ‘Euroxy’, and Cancer Research UK.
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 P. Philip-Couderc, N. I. Tavares, A. Roatti, R. Lerch, C. Montessuit, and A. J. Baertschi Forkhead Transcription Factors Coordinate Expression of Myocardial KATP Channel Subunits and Energy Metabolism Circ. Res., February 1, 2008; 102(2): e20 - e35. [Abstract] [Full Text] [PDF]
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 P. Hill, D. Shukla, M. G.B. Tran, J. Aragones, H. T. Cook, P. Carmeliet, and P. H. Maxwell Inhibition of Hypoxia Inducible Factor Hydroxylases Protects Against Renal Ischemia-Reperfusion Injury J. Am. Soc. Nephrol., January 1, 2008; 19(1): 39 - 46. [Abstract] [Full Text] [PDF]
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 D. J. Paterson Celebrating 100 years of publishing discovery in physiology 1908 - 2008 Exp Physiol, January 1, 2008; 93(1): 1 - 15. [Full Text] [PDF]
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 X.-H. Ning, E. Y. Chi, N. E. Buroker, S.-H. Chen, C.-S. Xu, Y.-T. Tien, O. M. Hyyti, M. Ge, and M. A. Portman Moderate hypothermia (30{degrees}C) maintains myocardial integrity and modifies response of cell survival proteins after reperfusion Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2119 - H2128. [Abstract] [Full Text] [PDF]
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 A.J. Harvey, K.L. Kind, and J.G. Thompson Regulation of Gene Expression in Bovine Blastocysts in Response to Oxygen and the Iron Chelator Desferrioxamine Biol Reprod, July 1, 2007; 77(1): 93 - 101. [Abstract] [Full Text] [PDF]
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 C. C. Wendler, S. Amatya, C. McClaskey, S. Ghatpande, B. B. Fredholm, and S. A. Rivkees A1 adenosine receptors play an essential role in protecting the embryo against hypoxia PNAS, June 5, 2007; 104(23): 9697 - 9702. [Abstract] [Full Text] [PDF]
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 T. R. Grover, T. M. Asikainen, J. P. Kinsella, S. H. Abman, and C. W. White Hypoxia-inducible factors HIF-1{alpha} and HIF-2{alpha} are decreased in an experimental model of severe respiratory distress syndrome in preterm lambs Am J Physiol Lung Cell Mol Physiol, June 1, 2007; 292(6): L1345 - L1351. [Abstract] [Full Text] [PDF]
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 S. Bonello, C. Zahringer, R. S. BelAiba, T. Djordjevic, J. Hess, C. Michiels, T. Kietzmann, and A. Gorlach Reactive Oxygen Species Activate the HIF-1{alpha} Promoter Via a Functional NF{kappa}B Site Arterioscler. Thromb. Vasc. Biol., April 1, 2007; 27(4): 755 - 761. [Abstract] [Full Text] [PDF]
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 M. Al-Asmakh, H. Race, S. Tan, and M.H.F. Sullivan The effects of oxygen concentration on in vitro output of prostaglandin E2 and interleukin-6 from human fetal membranes Mol. Hum. Reprod., March 1, 2007; 13(3): 197 - 201*. [Abstract] [Full Text] [PDF]
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 W. M. Bernhardt, M. S. Wiesener, A. Weidemann, R. Schmitt, W. Weichert, P. Lechler, V. Campean, A. C. M. Ong, C. Willam, N. Gretz, et al. Involvement of Hypoxia-Inducible Transcription Factors in Polycystic Kidney Disease Am. J. Pathol., March 1, 2007; 170(3): 830 - 842. [Abstract] [Full Text] [PDF]
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X.-H. Ning, S.-H. Chen, N. E. Buroker, C.-S. Xu, F.-R. Li, S.-P. Li, D.-S. Song, M. Ge, O. M. Hyyti, M. Zhang, et al. Short-cycle hypoxia in the intact heart: hypoxia-inducible factor 1{alpha} signaling and the relationship to injury threshold Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H333 - H341. [Abstract] [Full Text] [PDF]
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 Q. Lin, Y.-J. Lee, and Z. Yun Differentiation Arrest by Hypoxia J. Biol. Chem., October 13, 2006; 281(41): 30678 - 30683. [Abstract] [Full Text] [PDF]
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 N. Pore, A. K. Gupta, G. J. Cerniglia, Z. Jiang, E. J. Bernhard, S. M. Evans, C. J. Koch, S. M. Hahn, and A. Maity Nelfinavir Down-regulates Hypoxia-Inducible Factor 1{alpha} and VEGF Expression and Increases Tumor Oxygenation: Implications for Radiotherapy. Cancer Res., September 15, 2006; 66(18): 9252 - 9259. [Abstract] [Full Text] [PDF]
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