Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases

Nature Reviews Drug Discovery volume 13, pages 852–869 (2014)Cite this article

Subjects

Key Points

  • Hypoxia-inducible factors (HIFs) were originally described as transcription factors that promote transcriptional responses during hypoxia adaptation (for example, increased erythropoietin release following blood loss or during hypoxia). More recently, it has been appreciated that HIFs are also active during a wider range of disease conditions, including inflammation and ischaemia.

  • During inflammatory or ischaemic conditions, HIFs are stabilized and are transcriptionally active. In many instances, they promote a gene programme that dampens acute inflammation and that promotes resolution of injury.

  • During normoxic conditions, HIFs are inactive, as they are targeted for proteasomal degradation by prolyl hydroxylases (PHDs). During hypoxic conditions, PHDs are inactive, and HIFs become stabilized and transcriptionally active. Pharmacologically, HIFs can be stabilized by small molecules that function to inhibit PHDs. Such compounds have recently gained great interest.

  • Using pharmacological HIF activators (mostly PHD inhibitors), a HIF-dependent gene expression programme can be activated with the goal to dampen inflammation while promoting the resolution of injury. Examples for diseases for which there is experimental evidence indicating a protective role for HIF activators include inflammatory bowel disease (IBD), acute lung injury (ALI), myocardial ischaemia and reperfusion injury, acute kidney injury and organ transplantation.

  • Other studies have identified pharmacological approaches to inhibit HIFs. Such approaches could hold therapeutic potential in the treatment of cancer or fibrosis (for example, renal fibrosis).

  • Several companies have developed orally available PHD inhibitors that promote HIF stabilization under normoxic conditions. Such compounds are currently examined in clinical trials, for example, for the treatment of renal anaemia or perioperative ischaemia and reperfusion injury.

  • Although most clinical and experimental studies so far have found that short-term PHD inhibitor treatment is safe, careful monitoring for potentially detrimental side effects of PHD inhibitors will be crucial, particularly for their chronic application in patients. Potential side effects could include liver injury, sepsis, increased erythropoiesis or cancer.

  • Challenges for the field include a better understanding of the specific roles for individual HIF isoforms (for example, HIF1α and HIF2α), the design of pharmacological approaches to specifically target individual PHDs or individual HIFs, and pharmacological delivery systems that allow tissue-specific delivery of HIF activators (for example, via inhalation to alveolar epithelial cells or approaches to specifically target intestinal epithelial cells).

  • We anticipate that, in the near future, HIF activators will be used routinely in a clinical setting for organ protection in patients experiencing ischaemia and reperfusion injury, as well as to promote the resolution of inflammation during acute or chronic inflammatory disease states such as IBD or ALI.

Abstract

Hypoxia-inducible factors (HIFs) are stabilized during adverse inflammatory processes associated with disorders such as inflammatory bowel disease, pathogen infection and acute lung injury, as well as during ischaemia–reperfusion injury. HIF stabilization and hypoxia-induced changes in gene expression have a profound impact on the inflamed tissue microenvironment and on disease outcomes. Although the mechanism that initiates HIF stabilization may vary, the final molecular steps that control HIF stabilization converge on a set of oxygen-sensing prolyl hydroxylases (PHDs) that mark HIFs for proteasomal degradation. PHDs are therefore promising therapeutic targets. In this Review, we discuss the emerging potential and associated challenges of targeting the PHD–HIF pathway for the treatment of inflammatory and ischaemic diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Molecular mechanism of oxygen sensing and signalling.
Figure 2: PHD inhibitor treatment of inflammatory bowel disease.
Figure 3: Mechanism of HIF1α stabilization during acute lung injury.
Figure 4: Structure of the prolyl hydroxylase inhibitor AKB-4924.

Similar content being viewed by others

References

  1. Taylor, C. T. & McElwain, J. C. Ancient atmospheres and the evolution of oxygen sensing via the hypoxia-inducible factor in metazoans. Physiology 25, 272–279 (2010).

    CAS  PubMed  Google Scholar 

  2. Semenza, G. L. & Wang, G. L. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol. Cell. Biol. 12, 5447–5454 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Wang, G., Jiang, B., Rue, E. & Semenza, G. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc. Natl Acad. Sci. USA 92, 5510–5514 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Firth, J. D., Ebert, B. L., Pugh, C. W. & Ratcliffe, P. J. Oxygen-regulated control elements in the phosphoglycerate kinase 1 and lactate dehydrogenase A genes: similarities with the erythropoietin 3′ enhancer. Proc. Natl Acad. Sci. USA 91, 6496–6500 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Semenza, G. L., Roth, P. H., Fang, H. M. & Wang, G. L. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J. Biol. Chem. 269, 23757–23763 (1994). Landmark paper that identified binding of a hypoxia-inducible transcription factor, which binds to the erythropietin promoter and was subsequently named HIF.

    CAS  PubMed  Google Scholar 

  6. Taylor, C. T. Interdependent roles for hypoxia inducible factor and nuclear factor-κB in hypoxic inflammation. J. Physiol. 586, 4055–4059 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Schofield, C. J. & Ratcliffe, P. J. Oxygen sensing by HIF hydroxylases. Nature Rev. Mol. Cell Biol. 5, 343–354 (2004).

    CAS  Google Scholar 

  8. Semenza, G. L. Hypoxia-inducible factors in physiology and medicine. Cell 148, 399–408 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Semenza, G. L. Oxygen sensing, homeostasis, and disease. N. Engl. J. Med. 365, 537–547 (2011).

    CAS  PubMed  Google Scholar 

  10. Eltzschig, H. K. & Eckle, T. Ischemia and reperfusion — from mechanism to translation. Nature Med. 17, 1391–1401 (2011).

    CAS  PubMed  Google Scholar 

  11. Eltzschig, H. K., Sitkovsky, M. V. & Robson, S. C. Purinergic signaling during inflammation. N. Engl. J. Med. 367, 2322–2333 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Eltzschig, H. K. & Carmeliet, P. Hypoxia and inflammation. N. Engl. J. Med. 364, 656–665 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhang, H. et al. Digoxin and other cardiac glycosides inhibit HIF-1α synthesis and block tumor growth. Proc. Natl Acad. Sci. USA 105, 19579–19586 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Kaelin, W. G. Jr & Ratcliffe, P. J. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol. Cell 30, 393–402 (2008).

    CAS  PubMed  Google Scholar 

  15. Semenza, G. L. Regulation of oxygen homeostasis by hypoxia-inducible factor 1. Physiology 24, 97–106 (2009).

    CAS  PubMed  Google Scholar 

  16. Maxwell, P. H. et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399, 271–275 (1999).

    CAS  PubMed  Google Scholar 

  17. Tanimoto, K., Makino, Y., Pereira, T. & Poellinger, L. Mechanism of regulation of the hypoxia-inducible factor-1α by the von Hippel-Lindau tumor suppressor protein. EMBO J. 19, 4298–4309 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Epstein, A. C. et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107, 43–54 (2001). Landmark paper that identified mammalian PHDs in their functional role of regulating the stability of HIF.

    CAS  PubMed  Google Scholar 

  19. Jaakkola, P. et al. Targeting of HIF-α to the von Hippel–Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292, 468–472 (2001).

    CAS  PubMed  Google Scholar 

  20. Lando, D., Peet, D. J., Whelan, D. A., Gorman, J. J. & Murray, L. W. Asparagine hydroxylation of the HIF transactivation domain: a hypoxic switch. Science 295, 858–861 (2002).

    CAS  PubMed  Google Scholar 

  21. Ema, M. et al. A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1α regulates the VEGF expression and is potentially involved in lung and vascular development. Proc. Natl Acad. Sci. USA 94, 4273–4278 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Gu, Y. Z., Moran, S. M., Hogenesch, J. B., Wartman, L. & Bradfield, C. A. Molecular characterization and chromosomal localization of a third α-class hypoxia inducible factor subunit, HIF3α. Gene Expr. 7, 205–213 (1998).

    CAS  PubMed  Google Scholar 

  23. Makino, Y., Kanopka, A., Wilson, W. J., Tanaka, H. & Poellinger, L. Inhibitory PAS domain protein (IPAS) is a hypoxia-inducible splicing variant of the hypoxia-inducible factor-3α locus. J. Biol. Chem. 277, 32405–32408 (2002).

    CAS  PubMed  Google Scholar 

  24. Makino, Y. et al. Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature 414, 550–554 (2001).

    CAS  PubMed  Google Scholar 

  25. Bruick, R. K. Oxygen sensing in the hypoxic response pathway: regulation of the hypoxia-inducible transcription factor. Genes Dev. 17, 2614–2623 (2003).

    CAS  PubMed  Google Scholar 

  26. Mikus, P. & Zundel, W. COPing with hypoxia. Semin. Cell Dev. Biol. 16, 462–473 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Boh, B. K., Smith, P. G. & Hagen, T. Neddylation-induced conformational control regulates cullin RING ligase activity in vivo. J. Mol. Biol. 409, 136–145 (2011).

    CAS  PubMed  Google Scholar 

  28. Soucy, T. A. et al. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature 458, 732–736 (2009).

    CAS  PubMed  Google Scholar 

  29. Khoury, J., Ibla, J. C., Neish, A. S. & Colgan, S. P. Antiinflammatory adaptation to hypoxia through adenosine-mediated cullin-1 deneddylation. J. Clin. Invest. 117, 703–711 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Ehrentraut, S. F. et al. Central role for endothelial human deneddylase-1/SENP8 in fine-tuning the vascular inflammatory response. J. Immunol. 190, 392–400 (2013).

    CAS  PubMed  Google Scholar 

  31. Abraham, C. & Cho, J. H. Inflammatory bowel disease. N. Engl. J. Med. 361, 2066–2078 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Colgan, S. P. & Eltzschig, H. K. Adenosine and hypoxia-inducible factor signaling in intestinal injury and recovery. Annu. Rev. Physiol. 74, 153–175 (2012).

    CAS  PubMed  Google Scholar 

  33. Colgan, S. P. & Taylor, C. T. Hypoxia: an alarm signal during intestinal inflammation. Nature Rev. Gastroenterol. Hepatol 7, 281–287 (2010).

    Google Scholar 

  34. Karhausen, J. O. et al. Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis. J. Clin. Invest. 114, 1098–1106 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Clambey, E. T. et al. Hypoxia-inducible factor-1α-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proc. Natl Acad. Sci. USA 109, E2784–E2793 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Peyssonnaux, C. et al. Cutting edge: essential role of hypoxia inducible factor-1α in development of lipopolysaccharide-induced sepsis. J. Immunol. 178, 7516–7519 (2007).

    CAS  PubMed  Google Scholar 

  37. Kuhlicke, J., Frick, J. S., Morote-Garcia, J. C., Rosenberger, P. & Eltzschig, H. K. Hypoxia inducible factor (HIF)-1 coordinates induction of Toll-like receptors TLR2 and TLR6 during hypoxia. PLoS ONE 2, e1364 (2007).

    PubMed  PubMed Central  Google Scholar 

  38. Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496, 238–242 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Werth, N. et al. Activation of hypoxia inducible factor 1 is a general phenomenon in infections with human pathogens. PLoS ONE 5, e11576 (2010).

    PubMed  PubMed Central  Google Scholar 

  40. Hartmann, H. et al. Hypoxia-independent activation of HIF-1 by enterobacteriaceae and their siderophores. Gastroenterology 134, 756–767 (2008).

    CAS  PubMed  Google Scholar 

  41. Kempf, V. A. et al. Activation of hypoxia-inducible factor-1 in bacillary angiomatosis: evidence for a role of hypoxia-inducible factor-1 in bacterial infections. Circulation 111, 1054–1062 (2005).

    CAS  PubMed  Google Scholar 

  42. Haeberle, H. A. et al. Oxygen-independent stabilization of hypoxia inducible factor (HIF)-1 during RSV infection. PLoS ONE 3, e3352 (2008).

    PubMed  PubMed Central  Google Scholar 

  43. Nizet, V. & Johnson, R. S. Interdependence of hypoxic and innate immune responses. Nature Rev. Immunol. 9, 609–617 (2009).

    CAS  Google Scholar 

  44. Peyssonnaux, C. et al. HIF-1α expression regulates the bactericidal capacity of phagocytes. J. Clin. Invest. 115, 1806–1815 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Rius, J. et al. NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α. Nature 453, 807–811 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Grocott, M. P. et al. Arterial blood gases and oxygen content in climbers on Mount Everest. N. Engl. J. Med. 360, 140–149 (2009).

    CAS  PubMed  Google Scholar 

  47. Hartmann, G. et al. High altitude increases circulating interleukin-6, interleukin-1 receptor antagonist and C-reactive protein. Cytokine 12, 246–252 (2000).

    CAS  PubMed  Google Scholar 

  48. Synnestvedt, K. et al. Ecto-5′-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia. J. Clin. Invest. 110, 993–1002 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Schmit, M. A. et al. Vasodilator phosphostimulated protein (VASP) protects endothelial barrier function during hypoxia. Inflammation 35, 566–573 (2012).

    CAS  PubMed  Google Scholar 

  50. Cummins, E. P. et al. Prolyl hydroxylase-1 negatively regulates IκB kinase-β, giving insight into hypoxia-induced NFκB activity. Proc. Natl Acad. Sci. USA 103, 18154–18159 (2006). An important study that identified a functional role of PHDs in the stabilization of nuclear factor κB under hypoxic conditions.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Campbell, E. L. et al. Transmigrating neutrophils shape the mucosal microenvironment through localized oxygen depletion to influence resolution of inflammation. Immunity 40, 66–77 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Xavier, R. J. & Podolsky, D. K. Unravelling the pathogenesis of inflammatory bowel disease. Nature 448, 427–434 (2007).

    CAS  PubMed  Google Scholar 

  53. Marks, D. J., Rahman, F. Z., Sewell, G. W. & Segal, A. W. Crohn's disease: an immune deficiency state. Clin. Rev. Allergy Immunol. 38, 20–31 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Taylor, C. T. & Colgan, S. P. Hypoxia and gastrointestinal disease. J. Mol. Med. 85, 1295–1300 (2007).

    PubMed  Google Scholar 

  55. Huang, J. S. et al. Chronic granulomatous disease caused by a deficiency in p47(phox) mimicking Crohn's disease. Clin. Gastroenterol. Hepatol. 2, 690–695 (2004).

    CAS  PubMed  Google Scholar 

  56. Hart, M. L. et al. Hypoxia-inducible factor-1α-dependent protection from intestinal ischemia/reperfusion injury involves ecto-5′-nucleotidase (CD73) and the A2B adenosine receptor. J. Immunol. 186, 4367–4374 (2011).

    CAS  PubMed  Google Scholar 

  57. Xue, X. et al. Endothelial PAS domain protein 1 activates the inflammatory response in the intestinal epithelium to promote colitis in mice. Gastroenterology 145, 831–841 (2013).

    CAS  PubMed  Google Scholar 

  58. Tambuwala, M. M. et al. Loss of prolyl hydroxylase-1 protects against colitis through reduced epithelial cell apoptosis and increased barrier function. Gastroenterology 139, 2093–2101 (2010).

    CAS  PubMed  Google Scholar 

  59. Shah, Y. M. et al. Hypoxia-inducible factor augments experimental colitis through an MIF-dependent inflammatory signaling cascade. Gastroenterology 134, 2036–2048 (2008).

    PubMed  Google Scholar 

  60. Aherne, C. M. et al. Neuronal guidance molecule netrin-1 attenuates inflammatory cell trafficking during acute experimental colitis. Gut 61, 695–705 (2012).

    CAS  PubMed  Google Scholar 

  61. Frick, J. S. et al. Contribution of adenosine A2B receptors to inflammatory parameters of experimental colitis. J. Immunol. 182, 4957–4964 (2009).

    CAS  PubMed  Google Scholar 

  62. Eltzschig, H. K., Rivera-Nieves, J. & Colgan, S. P. Targeting the A2B adenosine receptor during gastrointestinal ischemia and inflammation. Expert Opin. Ther. Targets 13, 1267–1277 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Ehrentraut, H. et al. CD73+ regulatory T cells contribute to adenosine-mediated resolution of acute lung injury. FASEB J. 27, 2207–2219 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Ehrentraut, H., Westrich, J. A., Eltzschig, H. K. & Clambey, E. T. Adora2b adenosine receptor engagement enhances regulatory T cell abundance during endotoxin-induced pulmonary inflammation. PLoS ONE 7, e32416 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Xiao, C. & Rajewsky, K. MicroRNA control in the immune system: basic principles. Cell 136, 26–36 (2009).

    CAS  PubMed  Google Scholar 

  66. Fraisl, P., Aragones, J. & Carmeliet, P. Inhibition of oxygen sensors as a therapeutic strategy for ischaemic and inflammatory disease. Nature Rev. Drug Discov. 8, 139–152 (2009).

    CAS  Google Scholar 

  67. Cummins, E. P. et al. The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis. Gastroenterology 134, 156–165 (2008).

    CAS  PubMed  Google Scholar 

  68. Robinson, A. et al. Mucosal protection by hypoxia-inducible factor prolyl hydroxylase inhibition. Gastroenterology 134, 145–155 (2008).

    CAS  PubMed  Google Scholar 

  69. Keely, S. et al. Contribution of epithelial innate immunity to systemic protection afforded by prolyl hydroxylase inhibition in murine colitis. Mucosal Immunol. 22, 114–123 (2013).

    Google Scholar 

  70. Yellon, D. M. & Hausenloy, D. J. Myocardial reperfusion injury. N. Engl. J. Med. 357, 1121–1135 (2007).

    CAS  PubMed  Google Scholar 

  71. Murry, C. E., Jennings, R. B. & Reimer, K. A. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74, 1124–1136 (1986).

    CAS  PubMed  Google Scholar 

  72. Kohler, D. et al. CD39/ectonucleoside triphosphate diphosphohydrolase 1 provides myocardial protection during cardiac ischemia/reperfusion injury. Circulation 116, 1784–1794 (2007).

    PubMed  Google Scholar 

  73. Eckle, T. et al. Cardioprotection by ecto-5′-nucleotidase (CD73) and A2B adenosine receptors. Circulation 115, 1581–1590 (2007).

    CAS  PubMed  Google Scholar 

  74. Eckle, T. et al. Systematic evaluation of a novel model for cardiac ischemic preconditioning in mice. Am. J. Physiol. Heart Circ. Physiol. 291, H2533–H2540 (2006).

    CAS  PubMed  Google Scholar 

  75. Eltzschig, H. K. Adenosine: an old drug newly discovered. Anesthesiology 111, 904–915 (2009).

    CAS  PubMed  Google Scholar 

  76. Eckle, T., Kohler, D., Lehmann, R., El Kasmi, K. C. & Eltzschig, H. K. Hypoxia-inducible factor-1 is central to cardioprotection: a new paradigm for ischemic preconditioning. Circulation 118, 166–175 (2008).

    CAS  PubMed  Google Scholar 

  77. Eltzschig, H. K., Bonney, S. K. & Eckle, T. Attenuating myocardial ischemia by targeting A2B adenosine receptors. Trends Mol. Med. 19, 345–354 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Eckle, T. et al. Adora2b-elicited Per2 stabilization promotes a HIF-dependent metabolic switch crucial for myocardial adaptation to ischemia. Nature Med. 18, 774–782 (2012).

    CAS  PubMed  Google Scholar 

  79. Botker, H. E. et al. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet 375, 727–734 (2010).

    PubMed  Google Scholar 

  80. Cai, Z., Luo, W., Zhan, H. & Semenza, G. L. Hypoxia-inducible factor 1 is required for remote ischemic preconditioning of the heart. Proc. Natl Acad. Sci. USA 110, 17462–17467 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Kharbanda, R. K., Nielsen, T. T. & Redington, A. N. Translation of remote ischaemic preconditioning into clinical practice. Lancet 374, 1557–1565 (2009).

    PubMed  Google Scholar 

  82. Ali, Z. A. et al. Remote ischemic preconditioning reduces myocardial and renal injury after elective abdominal aortic aneurysm repair: a randomized controlled trial. Circulation 116 (11 Suppl.), I98–I105 (2007).

    PubMed  Google Scholar 

  83. Eckle, T. et al. Crosstalk between the equilibrative nucleoside transporter ENT2 and alveolar Adora2b adenosine receptors dampens acute lung injury. FASEB J. 27, 3078–3089 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Schingnitz, U. et al. Signaling through the A2B adenosine receptor dampens endotoxin-induced acute lung injury. J. Immunol. 184, 5271–5279 (2010).

    CAS  PubMed  Google Scholar 

  85. Eckle, T., Koeppen, M. & Eltzschig, H. K. Role of extracellular adenosine in acute lung injury. Physiology 24, 298–306 (2009).

    CAS  PubMed  Google Scholar 

  86. Eckle, T. et al. A2B adenosine receptor dampens hypoxia-induced vascular leak. Blood 111, 2024–2035 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Eckle, T., Grenz, A., Laucher, S. & Eltzschig, H. K. A2B adenosine receptor signaling attenuates acute lung injury by enhancing alveolar fluid clearance in mice. J. Clin. Invest. 118, 3301–3315 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Dengler, V., Downey, G. P., Tuder, R. M., Eltzschig, H. K. & Schmidt, E. P. Neutrophil intercellular communication in acute lung injury: emerging roles of microparticles and gap junctions. Am. J. Respir. Cell. Mol. Biol. 49, 1–5 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Ware, L. B. & Matthay, M. A. The acute respiratory distress syndrome. N. Engl. J. Med. 342, 1334–1349 (2000).

    CAS  PubMed  Google Scholar 

  90. Ranieri, V. M. et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA 307, 2526–2533 (2012).

    PubMed  Google Scholar 

  91. Herridge, M. S. et al. Functional disability 5 years after acute respiratory distress syndrome. N. Engl. J. Med. 364, 1293–1304 (2011).

    CAS  PubMed  Google Scholar 

  92. Sitkovsky, M. & Lukashev, D. Regulation of immune cells by local-tissue oxygen tension: HIF1α and adenosine receptors. Nature Rev. Immunol. 5, 712–721 (2005).

    CAS  Google Scholar 

  93. Sitkovsky, M. V. et al. Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors. Annu. Rev. Immunol. 22, 657–682 (2004).

    CAS  PubMed  Google Scholar 

  94. Thiel, M. et al. Oxygenation inhibits the physiological tissue-protecting mechanism and thereby exacerbates acute inflammatory lung injury. PLoS Biol. 3, e174 (2005). An important study indicating that hyperoxic conditions — which may be necessary for the treatment of patients with ALI to maintain oxygenation of different tissues — can be detrimental via inhibition of anti-inflammatory and tissue-protective functions of HIFs.

    PubMed  PubMed Central  Google Scholar 

  95. Eckle, T. et al. HIF1A reduces acute lung injury by optimizing carbohydrate metabolism in the alveolar epithelium. PLoS Biol. 11, e1001665 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Kominsky, D. J., Campbell, E. L. & Colgan, S. P. Metabolic shifts in immunity and inflammation. J. Immunol. 184, 4062–4068 (2010).

    CAS  PubMed  Google Scholar 

  97. Cramer, T. et al. HIF-1α is essential for myeloid cell-mediated inflammation. Cell 112, 645–657 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Kojima, H. et al. Abnormal B lymphocyte development and autoimmunity in hypoxia-inducible factor 1α -deficient chimeric mice. Proc. Natl Acad. Sci. USA 99, 2170–2174 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Okumura, C. Y. et al. A new pharmacological agent (AKB-4924) stabilizes hypoxia inducible factor-1 (HIF-1) and increases skin innate defenses against bacterial infection. J. Mol. Med. 28, 1079–1089 (2012).

    Google Scholar 

  100. Warnecke, C. et al. Activation of the hypoxia-inducible factor-pathway and stimulation of angiogenesis by application of prolyl hydroxylase inhibitors. FASEB J. 17, 1186–1188 (2003).

    CAS  PubMed  Google Scholar 

  101. Schaible, B. et al. Hypoxia modulates infection of epithelial cells by Pseudomonas aeruginosa. PLoS ONE. 8, e56491 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Kelly, C. J. et al. Fundamental role for HIF-1α in constitutive expression of human βdefensin-1. Mucosal Immunol. 6, 6 (2013).

    Google Scholar 

  103. Pazgier, M., Hoover, D. M., Yang, D., Lu, W. & Lubkowski, J. Human β-defensins. Cell. Mol. Life Sci. 63, 1294–1313 (2006).

    CAS  PubMed  Google Scholar 

  104. Ganz, T. Defensins: antimicrobial peptides of innate immunity. Nature Rev. Immunol. 3, 710–720 (2003).

    CAS  Google Scholar 

  105. Schroeder, B. O. et al. Reduction of disulphide bonds unmasks potent antimicrobial activity of human β-defensin 1. Nature 469, 419–423 (2011).

    CAS  PubMed  Google Scholar 

  106. Harder, J., Bartels, J., Christophers, E. & Schroder, J. M. Isolation and characterization of human β-defensin-3, a novel human inducible peptide antibiotic. J. Biol. Chem. 276, 5707–5713 (2001).

    CAS  PubMed  Google Scholar 

  107. O'Neil, D. A. et al. Expression and regulation of the human β-defensins hBD-1 and hBD-2 in intestinal epithelium. J. Immunol. 163, 6718–6724 (1999).

    CAS  PubMed  Google Scholar 

  108. Zhao, C., Wang, I. & Lehrer, R. I. Widespread expression of β-defensin hBD-1 in human secretory glands and epithelial cells. FEBS Lett. 396, 319–322 (1996).

    CAS  PubMed  Google Scholar 

  109. Peyrin-Biroulet, L. et al. Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon. Proc. Natl Acad. Sci. USA 107, 8772–8777 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Kocsis, A. K. et al. Association of β-defensin 1 single nucleotide polymorphisms with Crohn's disease. Scand. J. Gastroenterol. 43, 299–307 (2008).

    CAS  PubMed  Google Scholar 

  111. Wehkamp, J. et al. Inducible and constitutive β-defensins are differentially expressed in Crohn's disease and ulcerative colitis. Inflamm. Bowel Dis. 9, 215–223 (2003).

    Google Scholar 

  112. Jurevic, R. J., Bai, M., Chadwick, R. B., White, T. C. & Dale, B. A. Single-nucleotide polymorphisms (SNPs) in human β-defensin 1: high-throughput SNP assays and association with Candida carriage in type I diabetics and nondiabetic controls. J. Clin. Microbiol. 41, 90–96 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Schaefer, A. S. et al. A 3′ UTR transition within DEFB1 is associated with chronic and aggressive periodontitis. Genes Immun. 11, 45–54 (2010).

    CAS  PubMed  Google Scholar 

  114. Ozturk, A., Famili, P. & Vieira, A. R. The antimicrobial peptide DEFB1 is associated with caries. J. Dent. Res. 89, 631–636 (2010).

    CAS  PubMed  Google Scholar 

  115. Peyssonnaux, C. et al. Critical role of HIF-1α in keratinocyte defense against bacterial infection. J. Invest. Dermatol. 128, 1964–1968 (2008).

    CAS  PubMed  Google Scholar 

  116. Steinbrech, D. S. et al. Fibroblast response to hypoxia: the relationship between angiogenesis and matrix regulation. J. Surg. Res. 84, 127–133 (1999).

    CAS  PubMed  Google Scholar 

  117. Tandara, A. A. & Mustoe, T. A. Oxygen in wound healing — more than a nutrient. World J. Surg. 28, 294–300 (2004).

    PubMed  Google Scholar 

  118. Furuta, G. T. et al. Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia. J. Exp. Med. 193, 1027–1034 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Louis, N. A. et al. Selective induction of mucin-3 by hypoxia in intestinal epithelia. J. Cell Biochem. 99, 1616–1627 (2006).

    CAS  PubMed  Google Scholar 

  120. Elson, D. A., Ryan, H. E., Snow, J. W., Johnson, R. & Arbeit, J. M. Coordinate up-regulation of hypoxia inducible factor (HIF)-1α and HIF-1 target genes during multi-stage epidermal carcinogenesis and wound healing. Cancer Res. 60, 6189–6195 (2000).

    CAS  PubMed  Google Scholar 

  121. Albina, J. E. et al. HIF-1 expression in healing wounds: HIF-1α induction in primary inflammatory cells by TNF-α. Am. J. Physiol. Cell Physiol. 281, C1971–1977 (2001).

    CAS  PubMed  Google Scholar 

  122. Shweiki, D., Itin, A., Soffer, D. & Keshet, E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359, 843–845 (1992).

    CAS  PubMed  Google Scholar 

  123. Glover, L. E. et al. Control of creatine metabolism by HIF is an endogenous mechanism of barrier regulation in colitis. Proc. Natl Acad. Sci. USA 110, 19820–19825 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Clavien, P. A., Petrowsky, H., DeOliveira, M. L. & Graf, R. Strategies for safer liver surgery and partial liver transplantation. N. Engl. J. Med. 356, 1545–1559 (2007).

    PubMed  Google Scholar 

  125. Pirenne, J. et al. Influence of ischemia-reperfusion injury on rejection after liver transplantation. Transplant. Proc. 29, 366–367 (1997).

    CAS  PubMed  Google Scholar 

  126. Watt, K. D., Lyden, E. R., Gulizia, J. M. & McCashland, T. M. Recurrent hepatitis C posttransplant: early preservation injury may predict poor outcome. Liver Transpl. 12, 134–139 (2006).

    PubMed  Google Scholar 

  127. Schneider, M. et al. Loss or silencing of the PHD1 prolyl hydroxylase protects livers of mice against ischemia/reperfusion injury. Gastroenterology 138, 1143–1154 (2010).

    CAS  PubMed  Google Scholar 

  128. Chouker, A. et al. In vivo hypoxic preconditioning protects from warm liver ischemia–reperfusion injury through the adenosine A2B receptor. Transplantation 94, 894–902 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Hart, M. L. et al. Extracellular adenosine production by ecto-5′-nucleotidase protects during murine hepatic ischemic preconditioning. Gastroenterology 135, 1739.e3–1750.e3 (2008).

    Google Scholar 

  130. Cheng, K. et al. Hypoxia-inducible factor-1α regulates β cell function in mouse and human islets. J. Clin. Invest. 120, 2171–2183 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Atkinson, M. A., Eisenbarth, G. S. & Michels, A. W. Type 1 diabetes. Lancet 383, 69–82 (2014).

    PubMed  Google Scholar 

  132. Kebir, H. et al. Human TH17 lymphocytes promote blood–brain barrier disruption and central nervous system inflammation. Nature Med. 13, 1173–1175 (2007).

    CAS  PubMed  Google Scholar 

  133. Dang, E. V. et al. Control of TH17/Treg balance by hypoxia-inducible factor 1. Cell 146, 772–784 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Shi, L. Z. et al. HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and TReg cells. J. Exp. Med. 208, 1367–1376 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. O'Connor, W. Jr et al. A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nature Immunol. 10, 603–609 (2009).

    CAS  Google Scholar 

  136. Ben-Shoshan, J., Maysel-Auslender, S., Mor, A., Keren, G. & George, J. Hypoxia controls CD4+CD25+ regulatory T-cell homeostasis via hypoxia-inducible factor-1α. Eur. J. Immunol. 38, 2412–2418 (2008).

    CAS  PubMed  Google Scholar 

  137. Bartels, K., Karhausen, J., Clambey, E. T., Grenz, A. & Eltzschig, H. K. Perioperative organ injury. Anesthesiology 119, 1474–1489 (2013).

    PubMed  Google Scholar 

  138. Park, S. W. et al. Paneth cell-mediated multiorgan dysfunction after acute kidney injury. J. Immunol. 189, 5421–5433 (2012).

    CAS  PubMed  Google Scholar 

  139. Gelman, S. The pathophysiology of aortic cross-clamping and unclamping. Anesthesiology 82, 1026–1060 (1995).

    CAS  PubMed  Google Scholar 

  140. Schrier, R. W. & Wang, W. Acute renal failure and sepsis. N. Engl. J. Med. 351, 159–169 (2004).

    CAS  PubMed  Google Scholar 

  141. Bove, T. et al. Renoprotective action of fenoldopam in high-risk patients undergoing cardiac surgery: a prospective, double-blind, randomized clinical trial. Circulation 111, 3230–3235 (2005).

    CAS  PubMed  Google Scholar 

  142. Kumar, A. B. & Suneja, M. Cardiopulmonary bypass-associated acute kidney injury. Anesthesiology 114, 964–970 (2011).

    PubMed  Google Scholar 

  143. Hill, P. et al. Inhibition of hypoxia inducible factor hydroxylases protects against renal ischemia-reperfusion injury. J. Am. Soc. Nephrol. 19, 39–46 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Grenz, A. et al. The reno-vascular A2B adenosine receptor protects the kidney from ischemia. PLoS Med. 5, e137 (2008).

    PubMed  PubMed Central  Google Scholar 

  145. Kapitsinou, P. P. et al. Endothelial HIF-2 mediates protection and recovery from ischemic kidney injury. J. Clin. Invest. 124, 2396–2409 (2014). An important study that, for the first time, implicates kidney protection by HIF2α expressed in vascular endothelial cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Mole, D. R. et al. 2-oxoglutarate analogue inhibitors of HIF prolyl hydroxylase. Bioorg. Med. Chem. Lett. 13, 2677–2680 (2003).

    CAS  PubMed  Google Scholar 

  147. Masson, N. & Ratcliffe, P. J. HIF prolyl and asparaginyl hydroxylases in the biological response to intracellular O2 levels. J. Cell Sci. 116, 3041–3049 (2003).

    CAS  PubMed  Google Scholar 

  148. Chan, D. A., Sutphin, P. D., Yen, S. E. & Giaccia, A. J. Coordinate regulation of the oxygen-dependent degradation domains of hypoxia-inducible factor 1α. Mol. Cell. Biol. 25, 6415–6426 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Kong, D. et al. Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Cancer Res. 65, 9047–9055 (2005).

    CAS  PubMed  Google Scholar 

  150. Wang, R., Zhou, S. & Li, S. Cancer therapeutic agents targeting hypoxia-inducible factor-1. Curr. Med. Chem. 18, 3168–3189 (2011).

    CAS  PubMed  Google Scholar 

  151. Xia, Y., Choi, H. K. & Lee, K. Recent advances in hypoxia-inducible factor (HIF)-1 inhibitors. Eur. J. Med. Chem. 49, 24–40 (2012).

    CAS  PubMed  Google Scholar 

  152. Ku, J. H. et al. Effect of dutasteride on the expression of hypoxia-inducible factor-1α, vascular endothelial growth factor and microvessel density in rat and human prostate tissue. Scand. J. Urol. Nephrol. 43, 445–453 (2009).

    CAS  PubMed  Google Scholar 

  153. Puppo, M. et al. Topotecan inhibits vascular endothelial growth factor production and angiogenic activity induced by hypoxia in human neuroblastoma by targeting hypoxia-inducible factor-1α and -2α. Mol. Cancer Ther. 7, 1974–1984 (2008).

    CAS  PubMed  Google Scholar 

  154. Palayoor, S. T. et al. PX-478, an inhibitor of hypoxia-inducible factor-1α, enhances radiosensitivity of prostate carcinoma cells. Int. J. Cancer 123, 2430–2437 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Rey, S. et al. Synergistic effect of HIF-1α gene therapy and HIF-1-activated bone marrow-derived angiogenic cells in a mouse model of limb ischemia. Proc. Natl Acad. Sci. USA 106, 20399–20404 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Aragones, J. et al. Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. Nature Genet. 40, 170–180 (2008). A study providing critically important insights into mechanisms of PHD-dependent tissue protection during ischaemia. Indeed, the authors found that PHD1 deletion and concomittant elevation in HIFs is associated with improved metabolic responses, thereby promoting hypoxia or ischaemia tolerance.

    CAS  PubMed  Google Scholar 

  157. Rajagopalan, S. et al. Use of a constitutively active hypoxia-inducible factor-1α transgene as a therapeutic strategy in no-option critical limb ischemia patients: Phase I dose-escalation experience. Circulation 115, 1234–1243 (2007).

    CAS  PubMed  Google Scholar 

  158. Creager, M. A. et al. Effect of hypoxia-inducible factor-1α gene therapy on walking performance in patients with intermittent claudication. Circulation 124, 1765–1773 (2011).

    CAS  PubMed  Google Scholar 

  159. Bernhardt, W. M. et al. Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD. J. Am. Soc. Nephrol. 21, 2151–2156 (2010). The first published clinical trial that successfully uses a PHD inhibitor in patients to achieve HIF stabilization and concomitant increases in erythropoitin production.

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Flight, M. H. Deal watch: AstraZeneca bets on FibroGen's anaemia drug. Nature Rev. Drug Discov. 12, 730 (2013).

    Google Scholar 

  161. Macdougall, I. C. New anemia therapies: translating novel strategies from bench to bedside. Am. J. Kidney Dis. 59, 444–451 (2012).

    PubMed  Google Scholar 

  162. Semenza, G. L. Targeting HIF-1 for cancer therapy. Nature Rev. Cancer 3, 721–732 (2003).

    CAS  Google Scholar 

  163. Kaelin, W. G. Von Hippel–Lindau disease. Annu. Rev. Pathol. 2, 145–173 (2007). An important review paper that summarizes the discovery and functional role of the VHL gene in the post-translational regulation of HIF levels.

    CAS  PubMed  Google Scholar 

  164. Fraisl, P., Mazzone, M., Schmidt, T. & Carmeliet, P. Regulation of angiogenesis by oxygen and metabolism. Dev. Cell 16, 167–179 (2009).

    CAS  PubMed  Google Scholar 

  165. Liao, D. & Johnson, R. S. Hypoxia: a key regulator of angiogenesis in cancer. Cancer Metastasis Rev. 26, 281–290 (2007).

    CAS  PubMed  Google Scholar 

  166. Pouyssegur, J., Dayan, F. & Mazure, N. M. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441, 437–443 (2006).

    CAS  PubMed  Google Scholar 

  167. Mazzone, M. et al. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 136, 839–851 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Galluzzi, L., Kepp, O., Heiden, M. G. & Kroemer, G. Metabolic targets for cancer therapy. Nature Rev. Drug Discov. 12, 829–846 (2013).

    CAS  Google Scholar 

  169. Semenza, G. L. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29, 625–634 (2009).

    PubMed  PubMed Central  Google Scholar 

  170. Asikainen, T. M. et al. Improved lung growth and function through hypoxia-inducible factor in primate chronic lung disease of prematurity. FASEB J. 20, 1698–1700 (2006).

    CAS  PubMed  Google Scholar 

  171. Hams, E. et al. The hydroxylase inhibitor dimethyloxallyl glycine attenuates endotoxic shock via alternative activation of macrophages and IL-10 production by B1 cells. Shock 36, 295–302 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Percy, M. J. et al. A gain-of-function mutation in the HIF2A gene in familial erythrocytosis. N. Engl. J. Med. 358, 162–168 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Simonson, T. S. et al. Genetic evidence for high-altitude adaptation in Tibet. Science 329, 72–75 (2010).

    CAS  PubMed  Google Scholar 

  174. Higgins, D. F. et al. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J. Clin. Invest. 117, 3810–3820 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Kastelein, J. J. et al. Potent reduction of apolipoprotein B and low-density lipoprotein cholesterol by short-term administration of an antisense inhibitor of apolipoprotein B. Circulation 114, 1729–1735 (2006).

    CAS  PubMed  Google Scholar 

  176. Takeda, N. et al. Differential activation and antagonistic function of HIF-α isoforms in macrophages are essential for NO homeostasis. Genes Dev. 24, 491–501 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Keith, B., Johnson, R. S. & Simon, M. C. HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nature Rev. Cancer 12, 9–22 (2012).

    CAS  Google Scholar 

  178. Branco-Price, C. et al. Endothelial cell HIF-1α and HIF-2α differentially regulate metastatic success. Cancer Cell 21, 52–65 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Scholz, C. C. et al. Regulation of IL-1β-induced NF-κB by hydroxylases links key hypoxic and inflammatory signaling pathways. Proc. Natl Acad. Sci. USA 110, 18490–18495 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Cockman, M. E. et al. Posttranslational hydroxylation of ankyrin repeats in IκB proteins by the hypoxia-inducible factor (HIF) asparaginyl hydroxylase, factor inhibiting HIF (FIH). Proc. Natl Acad. Sci. USA 103, 14767–14772 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Zaph, C. et al. Epithelial-cell-intrinsic IKK-β expression regulates intestinal immune homeostasis. Nature 446, 552–556 (2007).

    CAS  PubMed  Google Scholar 

  182. Coleman, M. L. et al. Asparaginyl hydroxylation of the Notch ankyrin repeat domain by factor inhibiting hypoxia-inducible factor. J. Biol. Chem. 282, 24027–24038 (2007).

    CAS  PubMed  Google Scholar 

  183. Koditz, J. et al. Oxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensor. Blood 110, 3610–3617 (2007).

    PubMed  Google Scholar 

  184. Bartels, K., Grenz, A. & Eltzschig, H. K. Hypoxia and inflammation are two sides of the same coin. Proc. Natl Acad. Sci. USA 110, 18351–18352 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Riegel, A. K. et al. Selective induction of endothelial P2Y6 nucleotide receptor promotes vascular inflammation. Blood 117, 2548–2555 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Idzko, M., Ferrari, D. & Eltzschig, H. K. Nucleotide signalling during inflammation. Nature 509, 310–317 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Koeppen, M., Eckle, T. & Eltzschig, H. K. Interplay of hypoxia and A2B adenosine receptors in tissue protection. Adv. Pharmacol. 61, 145–186 (2011).

    CAS  PubMed  Google Scholar 

  188. Aherne, C. M., Kewley, E. M. & Eltzschig, H. K. The resurgence of A2B adenosine receptor signaling. Biochim. Biophys. Acta 1808, 1329–1339 (2011).

    CAS  PubMed  Google Scholar 

  189. Faigle, M., Seessle, J., Zug, S., El Kasmi, K. C. & Eltzschig, H. K. ATP release from vascular endothelia occurs across Cx43 hemichannels and is attenuated during hypoxia. PLoS ONE 3, e2801 (2008).

    PubMed  PubMed Central  Google Scholar 

  190. Eltzschig, H. K. et al. ATP release from activated neutrophils occurs via connexin 43 and modulates adenosine-dependent endothelial cell function. Circ. Res. 99, 1100–1108 (2006).

    CAS  PubMed  Google Scholar 

  191. Hart, M. L., Gorzolla, I. C., Schittenhelm, J., Robson, S. C. & Eltzschig, H. K. SP1-dependent induction of CD39 facilitates hepatic ischemic preconditioning. J. Immunol. 184, 4017–4024 (2010).

    CAS  PubMed  Google Scholar 

  192. Eltzschig, H. K. et al. Central role of Sp1-regulated CD39 in hypoxia/ischemia protection. Blood 113, 224–232 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Thompson, L. F. et al. Crucial role for ecto-5′- nucleotidase (CD73) in vascular leakage during hypoxia. J. Exp. Med. 200, 1395–1405 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Ahmad, A. et al. Adenosine A2A receptor is a unique angiogenic target of HIF-2α in pulmonary endothelial cells. Proc. Natl Acad. Sci. USA 106, 10684–10689 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Kong, T., Westerman, K. A., Faigle, M., Eltzschig, H. K. & Colgan, S. P. HIF-dependent induction of adenosine A2B receptor in hypoxia. FASEB J. 20, 2242–2250 (2006).

    CAS  PubMed  Google Scholar 

  196. Morote-Garcia, J. C., Rosenberger, P., Nivillac, N. M., Coe, I. R. & Eltzschig, H. K. Hypoxia-inducible factor-dependent repression of equilibrative nucleoside transporter 2 attenuates mucosal inflammation during intestinal hypoxia. Gastroenterology 136, 607–618 (2009).

    CAS  PubMed  Google Scholar 

  197. Eltzschig, H. K. et al. HIF-1-dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia. J. Exp. Med. 202, 1493–1505 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Casanello, P. et al. Equilibrative nucleoside transporter 1 expression is downregulated by hypoxia in human umbilical vein endothelium. Circ. Res. 97, 16–24 (2005).

    CAS  PubMed  Google Scholar 

  199. Morote-Garcia, J. C., Rosenberger, P., Kuhlicke, J. & Eltzschig, H. K. HIF-1-dependent repression of adenosine kinase attenuates hypoxia-induced vascular leak. Blood 111, 5571–5580 (2008).

    CAS  PubMed  Google Scholar 

  200. Chan, D. A., Sutphin, P. D., Denko, N. C. & Giaccia, A. J. Role of prolyl hydroxylation in oncogenically stabilized hypoxia-inducible factor-1α. J. Biol. Chem. 277, 40112–40117 (2002).

    CAS  PubMed  Google Scholar 

  201. McDonough, M. A. et al. Selective inhibition of factor inhibiting hypoxia-inducible factor. J. Am. Chem. Soc. 127, 7680–7681 (2005).

    CAS  PubMed  Google Scholar 

  202. Wang, G. L. & Semenza, G. L. Desferrioxamine induces erythropoietin gene expression and hypoxia-inducible factor 1 DNA-binding activity: implications for models of hypoxia signal transduction. Blood. 82, 3610–3615 (1993).

    CAS  PubMed  Google Scholar 

  203. Knowles, H. J., Tian, Y. M., Mole, D. R. & Harris, A. L. Novel mechanism of action for hydralazine: induction of hypoxia-inducible factor-1α, vascular endothelial growth factor, and angiogenesis by inhibition of prolyl hydroxylases. Circ. Res. 95, 162–169 (2004).

    CAS  PubMed  Google Scholar 

  204. Ivan, M. et al. Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proc. Natl Acad. Sci. USA 99, 13459–13464 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Nangaku, M. et al. A novel class of prolyl hydroxylase inhibitors induces angiogenesis and exerts organ protection against ischemia. Arterioscler. Thromb. Vasc. Biol. 27, 2548–2554 (2007).

    CAS  PubMed  Google Scholar 

  206. Zaman, K. et al. Protection from oxidative stress-induced apoptosis in cortical neuronal cultures by iron chelators is associated with enhanced DNA binding of hypoxia-inducible factor-1 and ATF-1/CREB and increased expression of glycolytic enzymes, 21(waf1/cip1), and erythropoietin. J. Neurosci. 19, 9821–9830 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Warshakoon, N. C. et al. Design and synthesis of a series of novel pyrazolopyridines as HIF-1α prolyl hydroxylase inhibitors. Bioorg. Med. Chem. Lett. 16, 5687–5690 (2006).

    CAS  PubMed  Google Scholar 

  208. Choi, S. M. et al. Clioquinol, a Cu(II)/Zn(II) chelator, inhibits both ubiquitination and asparagine hydroxylation of hypoxia-inducible factor-1α, leading to expression of vascular endothelial growth factor and erythropoietin in normoxic cells. J. Biol. Chem. 281, 34056–34063 (2006).

    CAS  PubMed  Google Scholar 

  209. Siddiq, A. et al. Hypoxia-inducible factor prolyl 4-hydroxylase inhibition. A target for neuroprotection in the central nervous system. J. Biol. Chem. 280, 41732–41743 (2005).

    CAS  PubMed  Google Scholar 

  210. Jiang, B. H. et al. Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1. Cell Growth Differ. 12, 363–369 (2001).

    CAS  PubMed  Google Scholar 

  211. Majumder, P. K. et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1- dependent pathways. Nature Med. 10, 594–601 (2004).

    CAS  PubMed  Google Scholar 

  212. Mie Lee, Y. et al. Inhibition of hypoxia-induced angiogenesis by FK228, a specific histone deacetylase inhibitor, via suppression of HIF-1α activity. Biochem. Biophys. Res. Commun. 300, 241–246 (2003).

    PubMed  Google Scholar 

  213. Qian, D. Z. et al. Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1α. Cancer Res. 66, 8814–8821 (2006).

    CAS  PubMed  Google Scholar 

  214. Kong, X. et al. Histone deacetylase inhibitors induce VHL and ubiquitin-independent proteasomal degradation of hypoxia-inducible factor 1α. Mol. Cell. Biol. 26, 2019–2028 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. Hur, E. et al. Reduction of hypoxia-induced transcription through the repression of hypoxia-inducible factor-1α/aryl hydrocarbon receptor nuclear translocator DNA binding by the 90-kDa heat-shock protein inhibitor radicicol. Mol. Pharmacol. 62, 975–982 (2002).

    CAS  PubMed  Google Scholar 

  216. Osada, M., Imaoka, S. & Funae, Y. Apigenin suppresses the expression of VEGF, an important factor for angiogenesis, in endothelial cells via degradation of HIF-1α protein. FEBS Lett. 575, 59–63 (2004).

    CAS  PubMed  Google Scholar 

  217. Mabjeesh, N. J. et al. Geldanamycin induces degradation of hypoxia-inducible factor 1α protein via the proteosome pathway in prostate cancer cells. Cancer Res. 62, 2478–2482 (2002).

    CAS  PubMed  Google Scholar 

  218. Isaacs, J. S. et al. Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1α-degradative pathway. J. Biol. Chem. 277, 29936–29944 (2002).

    CAS  PubMed  Google Scholar 

  219. Kaluz, S., Kaluzova, M. & Stanbridge, E. J. Proteasomal inhibition attenuates transcriptional activity of hypoxia-inducible factor 1 (HIF-1) via specific effect on the HIF-1α C-terminal activation domain. Mol. Cell. Biol. 26, 5895–5907 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  220. Yeo, E. J. et al. Amphotericin B blunts erythropoietin response to hypoxia by reinforcing FIH-mediated repression of HIF-1. Blood. 107, 916–923 (2006).

    CAS  PubMed  Google Scholar 

  221. Kung, A. L. et al. Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway. Cancer Cell. 6, 33–43 (2004).

    CAS  PubMed  Google Scholar 

  222. Verma, R. P. & Hansch, C. Camptothecins: a SAR/QSAR study. Chem. Rev. 109, 213–235 (2009).

    CAS  PubMed  Google Scholar 

  223. Rapisarda, A. et al. Schedule-dependent inhibition of hypoxia-inducible factor-1α protein accumulation, angiogenesis, and tumor growth by topotecan in U251-HRE glioblastoma xenografts. Cancer Res. 64, 6845–6848 (2004).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge S. A. Eltzschig for artwork during the preparation of this manuscript. This work is supported by US National Institutes of Health grants (DK097075, HL092188, DK083385, HL098294, HL114457, DK50189, HL60569, DK95491 and HL119837) and by grants from the Crohn's and Colitis Foundation of America.

Author information

Authors and Affiliations

  1. Department of Anesthesiology, Organ Protection Program, University of Colorado School of Medicine, Aurora, 80045, Colorado, USA

    Holger K. Eltzschig

  2. Department of Pediatrics, National Jewish Health, Denver, 80206, Colorado, USA

    Donna L. Bratton

  3. Department of Medicine, Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, 80045, Colorado, USA

    Sean P. Colgan

Authors
  1. Holger K. Eltzschig
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Donna L. Bratton
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sean P. Colgan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Holger K. Eltzschig.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

FURTHER INFORMATION

ClinicalTrials.gov

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Eltzschig, H., Bratton, D. & Colgan, S. Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases. Nat Rev Drug Discov 13, 852–869 (2014). https://doi.org/10.1038/nrd4422

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd4422

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research