Skip to main page content
U.S. flag
See More

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2012 Feb 3;148(3):399-408.
doi: 10.1016/j.cell.2012.01.021.

Hypoxia-inducible factors in physiology and medicine

Gregg L Semenza  1
Affiliations
Review

Hypoxia-inducible factors in physiology and medicine

Gregg L Semenza. Cell. .

Abstract

Oxygen homeostasis represents an organizing principle for understanding metazoan evolution, development, physiology, and pathobiology. The hypoxia-inducible factors (HIFs) are transcriptional activators that function as master regulators of oxygen homeostasis in all metazoan species. Rapid progress is being made in elucidating homeostatic roles of HIFs in many physiological systems, determining pathological consequences of HIF dysregulation in chronic diseases, and investigating potential targeting of HIFs for therapeutic purposes.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Regulation of Glucose Metabolism
Under hypoxic conditions, HIF-1 activates the transcription of genes encoding: glucose transporters and glycolytic enzymes, which increase flux of glucose to pyruvate; PDK1 (encoding pyruvate dehydrogenase kinase), which inactivates PDH (pyruvate dehydrogenase), the mitochondrial enzyme that converts pyruvate to acetyl CoA for entry into the tricarboxylic acid (TCA/citric acid/Krebs) cycle; LDHA, which converts pyruvate to lactate; and BNIP3 and BNIP3L, which induce mitochondrial autophagy. The shunting of substrate away from the mitochondria reduces ATP production but prevents excess ROS production that occurs due to inefficient electron transport under hypoxic conditions.
Figure 2
Figure 2. Vascular Effects of Continuous and Intermittent Hypoxia
(A) Prolonged continuous alveolar hypoxia results in pulmonary arterial hypertension due to the activation of both HIF-1α and HIF-2α, leading to changes in pulmonary arterioles that reduce luminal diameter, thereby increasing pulmonary vascular resistance. (B) Chronic intermittent hypoxia results in systemic arterial hypertension due to activation of HIF-1α and degradation of HIF-2α. Increased HIF-1α-dependent expression of NADPH oxidase 2 (NOX2), which generates superoxide anion, and decreased HIF-2α-dependent expression of superoxide dismutase 2 (SOD2), which consumes superoxide, result in increased ROS levels in the carotid body, leading to sympathetic nervous system activation and systemic hypertension.
See this image and copyright information in PMC

References

    1. Beall CM, Cavalleri GL, Deng L, Elston RC, Gao Y, Knight J, Li C, Li JC, Liang Y, McCormack M, Montgomery HE, Pan H, Robbins PA, Shianna KV, Tam SC, Tsering N, Veeramah KR, Wang W, Wangdui P, Weale ME, Xu Y, Xu Z, Yang L, Zaman MJ, Zeng C, Zhang L, Zhang X, Zhaxi P, Zheng YT. Natural selection on EPAS1 (HIF-2α) associated with low hemoglobin concentration in Tibetan highlanders. Proc. Natl. Acad. Sci. USA. 2010;107:11459–11464. - PMC - PubMed
    1. Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouysségur J, Mazure NM. Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol. Cell. Biol. 2009;29:2570–2581. - PMC - PubMed
    1. Bernhardt WM, Gottmann U, Doyon F, Buchholz B, Campean V, Schödel J, Reisenbuechler A, Klaus S, Arend M, Flippin L, Willam C, Wiesener MS, Yard B, Warnecke C, Eckardt KU. Donor treatment with a PHD-inhibitor activating HIFs prevents graft injury and prolongs survival in an allogenic kidney transplant model. Proc. Natl. Acad. Sci. USA. 2009;106:21276–21281. - PMC - PubMed
    1. Bonnet S, Michelakis ED, Porter CJ, Andrade-Navarro MA, Thébaud B, Bonnet S, Haromy A, Harry G, Moudgil R, McMurtry MS, Weir EK, Archer SL. An abnormal mitochondrial-hypoxia inducible factor-1α-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: similarities to human pulmonary arterial hypertension. Circulation. 2006;113:2630–2641. - PubMed
    1. Bosch-Marcé M, Okuyama H, Wesley JB, Sarkar K, Kimura H, Liu YV, Zhang H, Strazza M, Rey S, Savino L, Zhou YF, McDonald KR, Na Y, Vandiver S, Rabi A, Shaked Y, Kerbel R, Lavallee T, Semenza GL. Effects of aging and hypoxia-inducible factor-1 activity on angiogenic cell mobilization and recovery of perfusion after limb ischemia. Circ. Res. 101:1310–1318. - PubMed

Publication types

Substances