The human side of hypoxia‐inducible factor

Abstract

Summary 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.

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    Wang J, Chen G, Muckenthaler M, Galy B, Hentze MW, Pantopoulos K. Iron-mediated degradation of IRP2, an unexpected pathway involving a 2-oxoglutarate-dependent oxygenase activity. Molecular and Cellular Biology. 2004;24:954-965.

    Not in our library10.1128/mcb.24.3.954-965.2004

94. 94.

    Wedzicha JA, Cotes PM, Empey DW, Newland AC, Royston JP, Tam RC. Serum immunoreactive erythropoietin in hypoxic lung disease with and without polycythaemia. Clinical Science. 1985;69:413-422.

    Not in our library10.1042/cs0690413

95. 95.

    Weir EK, Lopez-Barneo J, Buckler KJ, Archer SL. Acute oxygen-sensing mechanisms. New England Journal of Medicine. 2005;353:2042-2055.

    Not in our library10.1056/nejmra050002

96. 96.

    West JB. High Life: A History of High-Altitude Physiology and Medicine. 1998.

    Not in our library

97. 97.

    Wiesener MS, Turley H, Allen WE, Willam C, Eckardt KU, Talks KL, Wood SM, Gatter KC, Harris AL, Pugh CW, Ratcliffe PJ, Maxwell PH. Induction of endothelial PAS domain protein-1 by hypoxia: characterization and comparison with hypoxia-inducible factor-1α. Blood. 1998;92:2260-2268.

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98. 98.

    Winslow RM, Samaja M, West JB. Red cell function at extreme altitude on Mount Everest. Journal of Applied Physiology. 1984;56:109-116.

    Not in our library10.1152/jappl.1984.56.1.109

99. 99.

    Yu AY, Shimoda LA, Iyer NV, Huso DL, Sun X, McWilliams R, Beaty T, Sham JSK, Wiener CM, Sylvester JT, Semenza GL. Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α. Journal of Clinical Investigation. 1999;103:691-696.

    Not in our library10.1172/jci5912

100. 100.

     Yu F, White SB, Zhao Q, Lee FS. HIF-1α binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proceedings of the National Academy of Sciences U S A. 2001;98:9630-9635.

     Not in our library10.1073/pnas.181341498

101. 101.

     Ziaei S, Norrozi M, Faghihzadeh S, Jafarbegloo E. A randomised placebo-controlled trial to determine the effect of iron supplementation on pregnancy outcome in pregnant women with haemoglobin ≥ 13·2 g/dl. BJOG. 2007;114:684-688.

     Not in our library10.1111/j.1471-0528.2007.01325.x

Cited by papers we hold 2

• ANDDigest: a new web-based module of ANDSystem for the search of knowledge in the scientific literature · 2020
  Not checked
• The Many Facets of Erythropoietin Physiologic and Metabolic Response · 2020
  No notice

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