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  • Review Article
  • Published:

Inhibition of oxygen sensors as a therapeutic strategy for ischaemic and inflammatory disease

Nature Reviews Drug Discovery volume 8, pages 139–152 (2009)Cite this article

Key Points

  • This Review highlights the therapeutic potential of inhibitors of a novel class of oxygen sensors — prolyl hydroxylase domain-containing proteins (PHDs) and factor inhibiting HIF (FIH) — to treat inflammatory and ischaemic diseases.

  • Oxygen sensors destabilize hypoxia inducible factors (HIFs), which are molecules that execute the cellular response to hypoxia. Induction of this HIF programme is associated with enhanced angiogenesis. Inhibition of PHDs might therefore offer opportunities for therapeutic revascularization of ischaemic tissues.

  • Inhibition of PHD1 results in ischaemia tolerance of skeletal muscle and other tissues; this protection is attributed to an attenuation of oxidative damage.

  • Inhibition of PHDs bears resemblance to changes in metabolism observed in hibernating species. This raises the possibility of therapeutically inducing (via inhibiting PHDs) a state of hibernation in various organs, which would confer cytoprotection against transient ischaemic periods during surgical (for example, bypass operations) or transplantation procedures.

  • Ischaemic preconditioning (IPC), a stressful but non-damaging hypoxic stimulus, confers protection against a subsequent harmful ischaemic event. Recent data indicate that inhibition of PHDs can induce IPC in vivo and confer resistance to hypoxic events in cardiac and cerebral tissues.

  • Inhibition of PHDs is also cytoprotective during development of inflammatory bowel disease in a murine model of colitis.

  • Most currently available PHD/FIH inhibitors are non-selective. Therefore, there is a need to develop novel, more specific inhibitors for each of the PHD isoforms. We discuss recently developed PHD inhibitors, and also introduce alternative approaches to generate more selective PHD inhibitors.

Abstract

Cells in the human body need oxygen to function and survive, and severe deprivation of oxygen, as occurs in ischaemic heart disease and stroke, is a major cause of mortality. Nevertheless, other organisms, such as the fossorial mole rat or diving seals, have acquired the ability to survive in conditions of limited oxygen supply. Hypoxia tolerance also allows the heart to survive chronic oxygen shortage, and ischaemic preconditioning protects tissues against lethal hypoxia. The recent discovery of a new family of oxygen sensors — including prolyl hydroxylase domain-containing proteins 1–3 (PHD1–3) — has yielded exciting novel insights into how cells sense oxygen and keep oxygen supply and consumption in balance. Advances in understanding of the role of these oxygen sensors in hypoxia tolerance, ischaemic preconditioning and inflammation are creating new opportunities for pharmacological interventions for ischaemic and inflammatory diseases.

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Figure 1: Therapeutic potential of PHD and FIH inhibition.
Figure 2: PHD inhibitors promote therapeutic angiogenesis.
Figure 3: PHD inhibition, oxygen conformance and hypoxia tolerance.
Figure 4: PHD inhibition and myocardial hibernation.
Figure 5: Role of the PHD and HIF system in ischaemic preconditioning.
Figure 6: Mechanisms underlying PHD inhibition in inflammatory diseases.
Figure 7: Simplified schematic strategies to design novel PHD and FIH inhibitors.

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Acknowledgements

This work is supported, in part, by grant GOA2006/11/KULeuven from the University of Leuven, Belgium, Methusalem Program, KU Leuven; grant IUAP06/30 from the Federal Government Belgium; and grants FWO G.0265 and FWO G.0652 from the Flanders Research Foundation, Belgium. P.F. is supported by a postdoctoral fellowship from the Marie Curie Program of the European Commission.

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  1. Peter Fraisl and Julián Aragonés: These authors contributed equally to this work.

Authors and Affiliations

  1. Vesalius Research Center, VIB, K. U. Leuven, Campus Gasthuisberg, Herestraat 49, B-3000, Leuven, Belgium

    Peter Fraisl, Julián Aragonés & Peter Carmeliet

  2. Department of Immunology, Princess Hospital, Autonomous University of Madrid, 28006, Madrid, Spain

    Julián Aragonés

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Peter Carmeliet is a named inventor on patent application WO/2007/082899, which claims subject matter that is partially based on the results described in this article. Should the aforementioned patent application or any resulting patent be licensed, this may result in royalty payment to P.C.

Glossary

Angiogenesis

The growth of new blood vessels from pre-existing vessels. Angiogenesis is a normal process in growth and development, but also has a crucial role in the growth of tumours.

Ischaemic preconditioning

A stressful but non-damaging stimulus that confers protection against a subsequent harmful acute ischaemic insult.

Abnormalization

Describes blood vessels in tumours, which are often tortuous, leaky and non-homogeneous in size and shape.

Multidrug resistance 1

Multidrug resistance 1 (MDR1; also known as P-glycoprotein), is a transmembrane energy-dependent drug-efflux pump encoded by the gene ABCB1 in humans. By reducing intracellular drug levels, P-glycoprotein can contribute to multidrug resistance to chemotherapeutics.

Autophagy

The self-cannibalism of intracellular organelles.

Cytochrome c oxidase

A component of the oxidative phosphorylation machinery within the cell that normally binds oxygen.

Mitochondrial permeability transition pore

A protein pore that is formed in the inner membrane of mitochondria that can lead to mitochondrial swelling and cell death.

Siderophores

Iron-binding proteins of bacterial origin.

Adipogenesis

The development of fat precursor cells into mature white or brown fat tissue.

Osteoblast

Osteoblasts are mononucleate cells that are responsible for bone formation.

Polycythaemia

An abnormal increase in the number of blood cells (primarily red blood cells).

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Fraisl, P., Aragonés, J. & Carmeliet, P. Inhibition of oxygen sensors as a therapeutic strategy for ischaemic and inflammatory disease. Nat Rev Drug Discov 8, 139–152 (2009). https://doi.org/10.1038/nrd2761

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