How to cite this WIREs title:
WIREs Syst Biol Med

Impact Factor: 4.275

Systems biology of oxygen homeostasis

Advanced Review

Gregg L. Semenza, Nanduri R. Prabhakar, Debangshu Samanta

Published Online: Feb 21 2017

DOI: 10.1002/wsbm.1382

Full article on Wiley Online Library: HTML PDF

Can't access this content? Tell your librarian.

Metazoan species maintain oxygen homeostasis through the activity of hypoxia‐inducible factors, which are transcriptional activators that regulate the expression of hundreds of genes to match O2 supply and demand. Here, we review the involvement of hypoxia‐inducible factors in the molecular physiology and pathophysiology of cellular O2 sensing, O2 delivery, O2 utilization, and systemic O2 sensing. WIREs Syst Biol Med 2017, 9:e1382. doi: 10.1002/wsbm.1382 This article is categorized under: Biological Mechanisms > Metabolism Physiology > Mammalian Physiology in Health and Disease Physiology > Organismal Responses to Environment

O₂‐dependent hydroxylation of hypoxia‐inducible factor (HIF)‐α subunits. Hydroxylation of specific proline (Pro) and asparagine (Asn) residues promote von Hippel‐Lindau (VHL) binding and block P300/CBP binding, respectively. VHL recruits an E3‐ubiquitin protein ligase (BCCRE2) consisting of Elongin B, Elongin C, Cullin 2, RBX1, and an E2 ubiquitin ligase that ubiquitinates HIF‐α, thereby targeting the protein for proteasomal degradation.

[ Normal View | Magnified View ]

Chronic intermittent hypoxia disrupts redox and HIF balance, leading to sympathetic activation and hypertension. HIF, hypoxia‐inducible factor; mTOR, mammalian target of rapamycin; NOX, NADPH oxidase; PKC, Ca²⁺‐dependent protein kinase; SOD, superoxide dismutase.

[ Normal View | Magnified View ]

O₂ sensing and signaling by gas messengers in the carotid body. O₂ stimulates CO production, which inhibits H₂S production, thereby inhibiting glomus cell depolarization. ROS generated by CIH inhibit HO2 activity, probably by oxidation of Cys‐265, thereby increasing H₂S production and CSN activity. cGMP, cyclic GMP; CIH, chronic intermittent hypoxia; CSE, cystathionine–γ‐lyase; CSN, carotid sinus nerve; Cys‐265, cysteine residue 265; HO2, heme oxygenase 2; Homocys, homocysteine; PKG, cGMP‐dependent protein kinase; ROS, reactive oxygen species; sGC, soluble guanylate cyclase.

[ Normal View | Magnified View ]

Neural transmission of reflex arcs that result in changes in heart rate (HR), respiratory rate (RR), and blood pressure (BP) in response to depolarization of glomus cells in the carotid body (CB). AM, adrenal medulla; ASN, adrenal sympathetic nerve; CSN, carotid sinus nerve; CST, corticospinal tract; Epi, epinephrine; NE, norepinephrine; nTS, nucleus tractus solitarius; RVLM, rostral ventro‐lateral medulla; SG, sympathetic ganglion.

[ Normal View | Magnified View ]

Oxygen‐dependent regulation of antioxidant production by HIF‐1 in human breast cancer cells. Under hypoxic conditions, HIFs activate the transcription of PHGDH, PSAT1, and PSPH (red) to increase conversion of glucose to serine (serine synthesis pathway); and SHMT2, MTHFD2, and MTHFD1L (blue) to increase generation of mitochondrial NADPH (mitochondrial one‐carbon metabolism), which is required to convert glutathione from oxidized (GSSG) to reduced (GSH) form to protect against increased ROS generated by the electron transport chain (ETC). Genes encoding proteins that generate cytosolic NADPH are either not consistently induced [SHMT1, MTHFD1 (purple)] or actively repressed [G6PD (green)] under hypoxic conditions. G6PD, glucose‐6‐phosphate dehydrogenase; MTHFD, methylene tetrahydrofolate dehydrogenase; MTHFD1L, MTHFD1‐like; PHGDH, phosphoglycerate dehydrogenase; PSAT, phosphoserine aminotransferase; PSPH, phosphoserine phosphatase; SHMT, serine hydroxymethyltransferase.

[ Normal View | Magnified View ]

Oxygen‐dependent regulation of oxidant production by hypoxia‐inducible factor (HIF)‐1. In hypoxic cells, HIF‐1 suppresses glucose oxidation, by activating the transcription of LDHA and PDK1 (blue), and fatty acid oxidation, by repressing the expression of MCAD and LCAD (green). In addition, under hypoxic conditions, HIF‐1 activates the transcription of BNIP3 (blue) to induce mitochondrial‐selective autophagy and thereby suppress both glucose and fatty acid oxidation. BNIP3, BCL2/adenovirus E1B 19‐kDa protein‐interacting protein 3; LCAD, long‐chain acyl‐CoA dehydrogenase; LDHA, lactate dehydrogenase A; MCAD, medium‐chain acyl‐CoA dehydrogenase; and PDK1, pyruvate dehydrogenase kinase 1.

[ Normal View | Magnified View ]

The hypoxia‐inducible factor (HIF) target genes VEGFA and ANGPTL4 encode secreted proteins that mediate angiogenesis and vascular permeability that leads to proliferative retinopathy and macular edema, respectively. Vascular endothelial growth factor A (VEGFA) binds to VEGFR2 on retinal vascular endothelial cells (VECs); the receptor for ANGPTL4 on retinal VECs has not been identified. Drugs inhibiting VEGFA binding to VEGFR2 on VECs are used to treat ocular diseases; inhibition of HIF activity or ANGPTL4 binding to its receptor on retinal VECs may also have therapeutic utility.

[ Normal View | Magnified View ]

Hypoxia‐inducible factor (HIF)‐1 and HIF‐2 are master regulators of tissue vascularization. Eight genes activated by HIF‐1 and HIF‐2 encode secreted proteins (blue ovals) that bind to cognate receptors (red ovals) on vascular cells to stimulate angiogenesis and vascular remodeling in response to hypoxia/ischemia.

[ Normal View | Magnified View ]

Hypoxia‐inducible factor (HIF)‐2 is a master regulator of erythropoiesis. Eight genes activated by HIF‐2 encode protein products that are required for iron absorption, transport, and incorporation into hemoglobin for red blood cell production. CYBRD1, SLC11A2, and SLC40A1 are expressed in duodenal enterocytes; TF is expressed in hepatocytes; EPO is expressed in renal interstitial cells; EPOR, FECH, and TFRC are expressed in erythroid progenitors.

[ Normal View | Magnified View ]

References

Semenza, GL. Oxygen homeostasis. WIREs Syst Biol Med 2010, 2:336–361.
Wang, GL, Jiang, BH, Rue, EA, Semenza, GL. Hypoxia‐inducible factor 1 is a basic‐helix‐loop‐helix‐PAS heterodimer regulated by cellular O₂ tension. Proc Natl Acad Sci USA 1995, 92:5510–5514.
Prabhakar, NR, Semenza, GL. Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia‐inducible factors 1 and 2. Physiol Rev 2012, 92:967–1003.
Duan, C. Hypoxia‐inducible factor 3 biology: complexities and emerging themes. Am J Physiol Cell Physiol 2016, 310:C260–C269.
Berra, E, Roux, D, Richard, DE, Pouysségur, J. Hypoxia‐inducible factor‐1α (HIF‐1α) escapes O₂‐driven proteasomal degradation irrespective of its subcellular localization: nucleus or cytoplasm. EMBO Rep 2001, 2:615–620.
Kaelin, WG Jr, Ratcliffe, PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 2008, 30:393–402.
Maxwell, PH, Wiesener, MS, Chang, GW, Clifford, SC, Vaux, EC, Cockman, ME, Wykoff, CC, Pugh, CW, Maher, ER, Ratcliffe, PJ. The tumor suppressor protein VHL targets hypoxia‐inducible factors for oxygen‐dependent proteolysis. Nature 1999, 399:271–275.
Ivan, M, Haberberger, T, Gervasi, DC, Michelson, KS, Günzler, V, Kondo, K, Yang, H, Sorokina, I, Conaway, RC, Conaway, JW, et al. Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia‐inducible factor. Proc Natl Acad Sci USA 2002, 99:13459–13464.
Waypa, GB, Smith, KA, Schumacker, PT. O₂ sensing, mitochondria and ROS signaling: the fog is lifting. Mol Aspects Med 2016, 47–48:76–89.
Lando, D, Peet, DJ, Whelan, DA, Gorman, JJ, Whitelaw, ML. Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science 2002, 295:858–861.
Mahon, PC, Hirota, K, Semenza, GL. FIH‐1: a novel protein that interacts with HIF‐1α and VHL to mediate repression of HIF‐1 transcriptional activity. Genes Dev 2001, 15:2675–2686.
Lando, D, Peet, DJ, Gorman, JJ, Whelan, DA, Whitelaw, ML, Bruick, RK. FIH‐1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia‐inducible factor. Genes Dev 2002, 16:1466–1471.
Dayan, F, Roux, D, Brahimi‐Horn, MC, Pouyssegur, J, Mazure, NM. The oxygen sensor factor‐inhibiting hypoxia‐inducible factor‐1 controls expression of distinct genes through the bifunctional transcriptional character of hypoxia‐inducible factor‐1α. Cancer Res 2006, 66:3688–3698.
Semenza, GL, Wang, GL. 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 1992, 12:5447–5454.
Yoon, D, Pastore, YD, Divoky, V, Liu, E, Mlodnicka, AE, Rainey, K, Ponka, P, Semenza, GL, Schumacher, A, Prchal, JT. Hypoxia‐inducible factor‐1 deficiency results in dysregulated erythropoiesis signaling and iron homeostasis in mouse development. J Biol Chem 2006, 281:25703–25711.
Shah, YM, Matsubara, T, Ito, S, Yim, SH, Gonzalez, FJ. Intestinal hypoxia‐inducible transcription factors are essential for iron absorption following iron deficiency. Cell Metab 2009, 9:152–164.
Mastrogiannaki, M, Matak, P, Keith, B, Simon, MC, Vaulont, S, Peyssonnaux, C. HIF‐2α, but not HIF‐1α, promotes iron absorption in mice. J Clin Invest 2009, 119:1159–1166.
Taylor, M, Qu, A, Anderson, ER, Matsubara, T, Martin, A, Gonzalez, FJ, Shah, YM. Hypoxia‐inducible factor 2α mediates the adaptive increased of intestinal ferroportin during iron deficiency in mice. Gastroenterology 2011, 140:2044–2055.
Rolfs, A, Kvietikova, I, Gassmann, M, Wenger, RH. Oxygen‐regulated transferrin expression is mediated by hypoxia‐inducible factor 1. J Biol Chem 1997, 272:20055–20062.
Lok, CN, Ponka, P. Identification of a hypoxia response element in the transferrin receptor gene. J Biol Chem 1999, 274:24147–24152.
Tacchini, L, Bianchi, L, Bernelli‐Zazzera, A, Cairo, G. Transferrin receptor induction by hypoxia. HIF‐1‐mediated transcriptional activation and cell‐specific post‐transcriptional regulation. J Biol Chem 1999, 274:24142–24146.
Liu, YL, Ang, SO, Weigent, DA, Prchal, JT, Bloomer, JR. Regulation of ferrochelatase gene expression by hypoxia. Life Sci 2004, 75:2035–2043.
Ang, SO, Chen, H, Hirota, K, Gordeuk, VR, Jelinek, J, Guan, Y, Liu, E, Sergueeva, AI, Miasnikova, GY, Mole, D, et al. Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nat Genet 2002, 32:614–621.
Smith, TG, Brooks, JT, Balanos, GM, Lappin, TR, Layton, DM, Leedham, DL, Liu, C, Maxwell, PH, McMullin, MF, McNamara, CJ, et al. Mutation of von Hippel‐Lindau tumor suppressor and human cardiopulmonary physiology. PLoS Med 2006, 3:e290.
Percy, MJ, Furlow, PW, Beer, PA, Lappin, TR, McMullin, MF, Lee, FS. A novel erythrocytosis‐associated PHD2 mutation suggests the location of a HIF binding groove. Blood 2007, 110:2193–2196.
Percy, MJ, Furlow, PW, Lucas, GS, Li, X, Lappin, TR, McMullin, MF, Lee, FS. A gain‐of‐function mutation in the HIF2A gene in familial erythrocytosis. N Engl J Med 2008, 358:162–168.
Formenti, F, Beer, PA, Croft, QP, Dorrington, KL, Gale, DP, Lappin, TR, Lucas, GS, Maher, ER, Maxwell, PH, McMullin, MF, et al. Cardiopulmonary function in two human disorders of the hypoxia‐inducible factor (HIF) pathway: von Hippel‐Lindau disease and HIF‐2α gain‐of‐function mutation. FASEB J 2011, 25:2001–2011.
Semenza, GL. Hypoxia‐inducible factor 1 and cardiovascular disease. Annu Rev Physiol 2014, 76:39–56.
Rey, S, Semenza, GL. Hypoxia‐inducible factor‐1‐dependent mechanisms of vascularization and vascular remodelling. Cardiovasc Res 2010, 86:236–242.
Bosch‐Marce, M, Okuyama, H, Wesley, JB, Sarkar, K, Kimura, H, Liu, YV, Zhang, H, Strazza, M, Rey, S, Savino, L, et al. Effects of aging and hypoxia‐inducible factor‐1 activity on angiogenic cell mobilization and recovery of perfusion after limb ischemia. Circ Res 2007, 101:1310–1318.
Sarkar, K, Fox‐Talbot, K, Steenbergen, C, Bosch‐Marcé, M, Semenza, GL. Adenoviral transfer of HIF‐1α enhances vascular responses to critical limb ischemia in diabetic mice. Proc Natl Acad Sci USA 2009, 106:18769–18774.
Rey, S, Lee, K, Wang, CJ, Gupta, K, Chen, S, McMillan, A, Bhise, N, Levchenko, A, Semenza, GL. 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 2009, 106:20399–20404.
Rey, S, Luo, W, Shimoda, LA, Semenza, GL. Metabolic reprogramming by HIF‐1 promotes the survival of bone marrow‐derived angiogenic cells in ischemic tissue. Blood 2011, 117:4988–4998.
Resar, JR, Roguin, A, Voner, J, Nasir, K, Hennebry, TA, Miller, JM, Ingersoll, R, Kasch, LM, Semenza, GL. Hypoxia‐inducible factor 1α polymorphism and coronary collaterals in patients with ischemic heart disease. Chest 2005, 128:787–791.
Hlatky, MA, Quertermous, T, Boothroyd, DB, Priest, JR, Glassford, AJ, Myers, RM, Fortmann, SP, Iribarren, C, Tabor, HK, Assimes, TL, et al. Polymorphisms in hypoxia‐inducible factor 1 and the initial clinical presentation of coronary disease. Am Heart J 2007, 154:1035–1042.
Campochiaro, PA. Ocular neovascularization. J Mol Med 2013, 91:311–321.
Aiello, LP, Avery, RL, Arrigg, PG, Keyt, BA, Jampel, HD, Shah, ST, Pasquale, LR, Thieme, H, Iwamoto, MA, Park, JE, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994, 331:1480–1487.
Ozaki, H, Yu, AY, Della, N, Ozaki, K, Luna, JD, Yamada, H, Hackett, SF, Okamoto, N, Zack, DJ, Semenza, GL, et al. Hypoxia inducible factor‐1α is increased in ischemic retina: temporal and spatial correlation with VEGF expression. Invest Ophthalmol Vis Sci 1999, 40:182–189.
Ip, MS, Domalpally, A, Hopkins, JJ, Wong, P, Ehrlich, JS. Long‐term effects of ranibizumab on diabetic retinopathy severity and progression. Arch Ophthalmol 2012, 130:1145–1152.
Yoshida, T, Zhang, H, Iwase, T, Shen, J, Semenza, GL, Campochiaro, PA. Digoxin inhibits retinal ischemia‐induced HIF‐1α expression and ocular neovascularization. FASEB J 2010, 24:1759–1767.
Babapoor‐Farrokhran, S, Jee, K, Puchner, B, Hassan, SJ, Xin, X, Rodrigues, M, Kashiwabuchi, F, Ma, T, Hu, K, Deshpande, M, et al. Angiopoietin‐like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy. Proc Natl Acad Sci USA 2015, 112:E3030–E3039.
Xin, X, Rodrigues, M, Umapathi, M, Kashiwabuchi, F, Ma, T, Babapoor‐Farrokhran, S, Wang, S, Hu, J, Bhutto, I, Welsbie, DS, et al. Hypoxic retinal Muller cells promote vascular permeability by HIF‐1‐dependent up‐regulation of angiopoietin‐like 4. Proc Natl Acad Sci USA 2013, 110:E3425–E3434.
Zhang, H, Qian, DZ, Tan, YS, Lee, K, Gao, P, Ren, YR, Rey, S, Hammers, H, Chang, D, Pili, R, et al. Digoxin and other cardiac glycosides inhibit HIF‐1α synthesis and block tumor growth. Proc Natl Acad Sci USA 2008, 105:19579–19586.
Lee, K, Qian, DZ, Rey, S, Wei, H, Liu, JO, Semenza, GL. Anthracycline chemotherapy inhibits HIF‐1 transcriptional activity and tumor‐induced mobilization of circulating angiogenic cells. Proc Natl Acad Sci USA 2009, 106:2353–2358.
Lee, K, Zhang, H, Qian, DZ, Rey, S, Liu, JO, Semenza, GL. Acriflavine inhibits HIF‐1 dimerization, tumor growth, and vascularization. Proc Natl Acad Sci USA 2009, 106:17910–17915.
Iwase, T, Fu, J, Yoshida, T, Muramatsu, D, Miki, A, Hashida, N, Lu, L, Oveson, B, Lima e Silva, R, Seidel, C, et al. Sustained delivery of a HIF‐1 antagonist for ocular neovascularization. J Control Release 2013, 172:625–633.
Vaupel, P, Hockel, M, Mayer, A. Detection and characterization of tumor hypoxia using pO₂ histography. Antioxid Redox Signal 2007, 9:1221–1235.
Carracedo, A, Cantley, LC, Pandolfi, PP. Cancer metabolism: fatty acid oxidation in the limelight. Nat Rev Cancer 2013, 13:227–232.
Semenza, GL. HIF‐1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J Clin Invest 2013, 123:3664–3671.
Kim, JW, Tchernyshyov, I, Semenza, GL, Dang, CV. HIF‐1‐mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 2006, 3:177–185.
Papandreou, I, Cairns, RA, Fontana, L, Denko, NC. HIF‐1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 2006, 3:187–197.
Lu, CW, Lin, SC, Chen, KF, Lai, YY, Tsai, SJ. Induction of pyruvate dehydrogenase kinase‐3 by hypoxia‐inducible factor 1 promotes metabolic switch and drug resistance. J Biol Chem 2008, 283:28106–28114.
Le, A, Cooper, CR, Gouw, AM, Dinavahi, R, Maitra, A, Deck, LM, Royer, RE, Vander Jagt, DL, Semenza, GL, Dang, CV. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci USA 2010, 107:2037–2042.
Zhang, H, Bosch‐Marce, M, Shimoda, LA, Tan, YS, Baek, JH, Wesley, JB, Gonzalez, FJ, Semenza, GL. Mitochondrial autophagy is an HIF‐1‐dependent adaptive metabolic response to hypoxia. J Biol Chem 2008, 283:10892–10903.
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.
Huang, D, Li, T, Li, X, Zhang, L, Sun, L, He, X, Zhong, X, Jia, D, Song, L, Semenza, GL, et al. HIF‐1‐mediated suppression of acyl‐CoA dehydrogenases and fatty acid oxidation is critical for cancer progression. Cell Rep 2014, 25:1930–1942.
Currie, E, Schulze, A, Zechner, R, Walther, TC, Farese, RV Jr. Cellular fatty acid metabolism and cancer. Cell Metab 2013, 18:153–161.
Samudio, I, Harmancey, R, Fiegl, M, Kantarjian, H, Konopleva, M, Korchin, B, Kaluarachchi, K, Bornmann, W, Duvvuri, S, Taegtmeyer, H, et al. Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J Clin Invest 2010, 120:142–156.
Camarda, R, Zhou, AY, Kohnz, RA, Balakrishnan, S, Mahieu, C, Anderton, B, Eyob, H, Kajimura, S, Krings, G, Nomura, DK, et al. Inhibition of fatty acid oxidation as a therapy for MYC‐overexpressing triple‐negative breast cancer. Nat Med 2016, 22:427–432.
Fan, J, Ye, J, Kamphorst, JJ, Shlomi, T, Thompson, CB, Rabinowitz, JD. Quantitative flux analysis reveals folate‐dependent NADPH production. Nature 2014, 510:298–302.
Samanta, D, Park, Y, Andrabi, SA, Shelton, LM, Gilkes, DM, Semenza, GL. PHGDH expression is required for mitochondrial redox homeostasis, breast cancer stem cell maintenance, and lung metastasis. Cancer Res 2016, 76:4430–4442.
Ye, J, Fan, J, Venneti, S, Wan, YW, Pawel, BR, Zhang, J, Finley, LW, Lu, C, Lindsten, T, Cross, JR, et al. Serine catabolism regulates mitochondrial redox control during hypoxia. Cancer Discov 2014, 4:1406–1417.
Kim, D, Fiske, BP, Birsoy, K, Freinkman, E, Kami, K, Possemato, RL, Chudnovsky, Y, Pacold, ME, Chen, WW, Cantor, JR, et al. SHMT2 drives glioma cell survival in ischemia but imposes a dependence on glycine clearance. Nature 2015, 520:363–367.
Lu, H, Samanta, D, Xiang, L, Zhang, H, Hu, H, Chen, I, Bullen, JW, Semenza, GL. Chemotherapy triggers HIF‐1‐dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype. Proc Natl Acad Sci USA 2015, 112:E4600–E4609.
Pflüger, E. Ueber die ursache der athembewegungen, sowie der dyspnoë und apnoë. Pflügers Arch Gesamte Physiol Meschen Tiere 1868, 1:61–106.
De Castro, F. Sur la structure et l`innervation de la glande intercarotidienne (glomus caroticum) de l`homme et des mammiferes et sur un nouveau systeme de l`innervation autonome du nerf glossopharyngien. Trav Lab Rech Biol 1926, 24:365–432.
Heymans, J, Heymans, C. Sur les modifications directes et sur la regulation reflexe de l`activitie du centre respiratory de la tete isolee du chien. Arch Int Pharmacodyn Ther 1927, 33:273–372.
Prabhakar, NR, Semenza, GL. Gaseous messengers in oxygen sensing. J Mol Med 2012, 90:265–272.
Prabhakar, NR, Semenza, GL. Oxygen sensing and homeostasis. Physiology 2015, 30:340–348.
Yuan, G, Vasavda, C, Peng, YJ, Makarenko, VV, Raghuraman, G, Nanduri, J, Gadalla, MM, Semenza, GL, Kumar, GK, Snyder, SH, et al. Protein kinase G‐regulated production of H₂S governs oxygen sensing. Sci Signal 2015, 8:ra37.
Peng, YJ, Nanduri, J, Raghuraman, G, Souvannakitti, D, Gadalla, MM, Kumar, GK, Snyder, SH, Prabhakar, NR. H₂S mediates O₂ sensing in the carotid body. Proc Natl Acad Sci USA 2010, 107:10719–10724.
Kline, DD, Peng, YJ, Manalo, DJ, Semenza, GL, Prabhakar, NR. Defective carotid body function and impaired ventilator responses to chronic hypoxia in mice partially deficient for hypoxia‐inducible factor 1α. Proc Natl Acad Sci USA 2002, 99:821–826.
Nieto, FJ, Young, TB, Lind, BK, Shahar, E, Samet, JM, Redline, S, D`Agostino, RB, Newman, AB, Lebowitz, MD, Pickering, TG. Association of sleep‐disordered breathing, sleep apnea, and hypertension in a large community‐based study. Sleep Heart Health Study. JAMA 2000, 283:1829–1836.
Fletcher, EC, Lesske, J, Behm, R, Miller, CC 3rd, Stauss, H, Unger, T. Carotid chemoreceptors, systemic blood pressure, and chronic episodic hypoxia mimicking sleep apnea. J Appl Physiol 1992, 72:1978–1984.
Peng, YJ, Yuan, G, Ramakrishnan, D, Sharma, SD, Bosch‐Marce, M, Kumar, GK, Semenza, GL, Prabhakar, NR. Heterozygous HIF‐1α deficiency impairs carotid body‐mediated systemic responses and reactive oxygen species generation in mice exposed to intermittent hypoxia. J Physiol 2006, 577:705–716.
Yuan, G, Khan, SA, Luo, W, Nanduri, J, Semenza, GL, Prabhakar, NR. Hypoxia‐inducible factor 1 mediates increased expression of NADPH oxidase‐2 in response to intermittent hypoxia. J Cell Physiol 2011, 226:2925–2933.
Yuan, G, Nanduri, J, Khan, S, Semenza, GL, Prabhakar, NR. Induction of HIF‐1α expression by intermittent hypoxia: involvement of NADPH oxidase, Ca²⁺ signaling, prolyl hydroxylases, and mTOR. J Cell Physiol 2008, 217:674–685.
Nanduri, J, Wang, N, Yuan, G, Khan, SA, Souvannakitti, D, Peng, YJ, Kumar, GK, Garcia, JA, Prabhakar, NR. Intermittent hypoxia degrades HIF‐2α via calpains resulting in oxidative stress: implications for recurrent apnea‐induced morbidities. Proc Natl Acad Sci USA 2009, 106:1199–1204.
Peng, YJ, Nanduri, J, Khan, SA, Yuan, G, Wang, N, Kinsman, B, Vaddi, DR, Kumar, GK, Garcia, JA, Semenza, GL, et al. Hypoxia‐inducible factor 2α (HIF‐2α) heterozygous‐ mice exhibit exaggerated carotid body sensitivity to hypoxia, breathing instability, and hypertension. Proc Natl Acad Sci USA 2011, 108:3065–3070.
Yuan, G, Peng, YJ, Reddy, VD, Makarenko, VV, Nanduri, J, Khan, SA, Garcia, JA, Kumar, GK, Semenza, GL, Prabhakar, NR. Mutual antagonism between hypoxia‐inducible factors 1α and 2α regulates oxygen sensing and cardio‐respiratory homeostasis. Proc Natl Acad Sci USA 2013, 110:E1788–E1796.
Yuan, G, Peng, YJ, Khan, SA, Nanduri, J, Singh, A, Vasavda, C, Semenza, GL, Kumar, GK, Snyder, SH, Prabhakar, NR. H₂S production by reactive oxygen species in the carotid body triggers hypertension in a rodent model of sleep apnea. Sci Signal 2016, 9:ra80.
Iyer, NV, Kotch, LE, Agani, F, Leung, SW, Laughner, E, Wenger, RH, Gassmann, M, Gearhart, JD, Lawler, AM, Yu, AY, et al. Cellular and developmental control of O₂ homeostasis by hypoxia‐inducible factor 1α. Genes Dev 1998, 12:149–162.
Maxwell, PH, Eckardt, KU. HIF prolyl hydroxylase inhibitors for the treatment of renal anemia and beyond. Nat Rev Nephrol 2016, 12:157–168.
Semenza, GL. The hypoxic tumor microenvironment: a driving force for breast cancer progression. Biochim Biophys Acta 2016, 1863:382–391.

Other Versions

Previous Versions

Oxygen homeostasis
Gregg L. Semenza
Published Online: April 09 2010
DOI: 10.1002/wsbm.69

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

The latest WIREs articles in your inbox

Sign Up for Article Alerts