Physiological and pathological responses to hypoxia
Open accessAbstract
As the average age in many countries steadily rises, heart infarction, stroke, and cancer become the most common causes of death in the 21st century. The causes of these disorders are many and varied and include genetic predisposition and environmental influences, but they all share a common feature in that limitation of oxygen availability participates in the development of these pathological conditions. However, cells and organisms are able to trigger an adaptive response to hypoxic conditions that is aimed to help them to cope with these threatening conditions. This review provides a description of several systems able to sense oxygen concentration and of the responses they initiate both in the acute and also in long-term hypoxia adaptation. The role of hypoxia in three pathological conditions, myocardial and cerebral ischemia as well as tumorigenesis, is briefly discussed.
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The Na/K-ATPase can account for 20-80% of oxygen expenditure in mammalian cells.
“A major consumer of cellular ATP is the Na/K-ATPase, which can account for 20–80% of oxygen expenditure in mammalian cells 21.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [21]
These metabolic findings are similar to those reported in other studies and are most likely attributed to a shift from aerobic respiration via oxidative phosphorylation to anaerobic respiration via glycolysis.
“These findings are similar to those reported in other studies and are most likely attributed to a shift from aerobic respiration via oxidative phosphorylation to anaerobic respiration via glycolysis [50–52].”
From Short-term physiological hypoxia potentiates the therapeutic function of mesenchymal stem cells (2018) · cites this paper as [52]
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Cites
Targeting HIF-1 for cancer therapy
Semenza, G. L. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1187 · Cited by 6,717 · see citing works
Jaakkola, P., Mole, D. R., Tian, Y.-M., Wilson, M. I., Gielbert, J., Gaskell, S. J., Kriegsheim, A. V., Hebestreit, H. F., Mukherji, M., Schofield, C. J., et al. (2001) · Science · doi:10.1126/science.1059796 · Cited by 5,535 · see citing works
Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J. M., Lane, W. S., & Kaelin Jr., W. G. (2001) · Science · doi:10.1126/science.1059817 · Cited by 4,735 · cited 1× · see citing works
“In the absence of oxygen, this enzyme is no longer active: the unmodified prolyl-HIF-1 does no longer interact with pVHL and accumulates.(32,33) The absolute requirement for oxygen of this prolyl hydroxylase indicates that this enzyme may function as a direct oxygen sensor.”
BackgroundMechanisms of angiogenesis and arteriogenesis
Carmeliet, P. (2000) · Nature Medicine · doi:10.1038/74651 · Cited by 4,146 · see citing works
The stunned myocardium: prolonged, postischemic ventricular dysfunction.
D, E. B. M., & Kloner, R. A. (1982) · Circulation · doi:10.1161/01.cir.66.6.1146 · Cited by 2,824 · see citing works
Cellular and developmental control of O <sub>2</sub> homeostasis by hypoxia-inducible factor 1α
Iyer, N. V., Kotch, L. E., Agani, F., Leung, S. W., Laughner, E., Wenger, R. H., Gassmann, M., Gearhart, J. D., Lawler, A. M., Yu, A. Y., et al. (1998) · Genes & Development · doi:10.1101/gad.12.2.149 · Cited by 2,476 · see citing works
(1999) · PubMed · Cited by 2,204 · see citing works
Cellular energy utilization and molecular origin of standard metabolic rate in mammals
Rolfe, D. F., & Brown, G. C. (1997) · Physiological Reviews · doi:10.1152/physrev.1997.77.3.731 · Cited by 2,021 · see citing works
Regulation of Mammalian O <sub>2</sub> Homeostasis by Hypoxia-Inducible Factor 1
Semenza, G. L. (1999) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.15.1.551 · Cited by 1,914 · see citing works
HIF‐1α is required for solid tumor formation and embryonic vascularization
Ryan, H. E., Lo, J., & Johnson, R. S. (1998) · The EMBO Journal · doi:10.1093/emboj/17.11.3005 · Cited by 1,579 · see citing works
Asparagine Hydroxylation of the HIF Transactivation Domain: A Hypoxic Switch
Lando, D., Peet, D. J., Whelan, D. A., Gorman, J. J., & Whitelaw, M. L. (2002) · Science · doi:10.1126/science.1068592 · Cited by 1,558 · see citing works
(2000) · PubMed · Cited by 1,445 · see citing works
Defense Strategies Against Hypoxia and Hypothermia
Hochachka, P. W. (1986) · Science · doi:10.1126/science.2417316 · Cited by 1,104 · see citing works
A hierarchy of ATP-consuming processes in mammalian cells
Buttgereit, F., & Brand, M. D. (1995) · Biochemical Journal · doi:10.1042/bj3120163 · Cited by 929 · see citing works
Marsin, A.-S., Bertrand, L., Rider, M. H., Deprez, J., Beauloye, C., Vincent, M. F., den Berghe, G. V., Carling, D., & Hue, L. (2000) · Current Biology · doi:10.1016/s0960-9822(00)00742-9 · Cited by 818 · see citing works
AMP‐activated protein kinase: the energy charge hypothesis revisited
Hardie, D. G., & Hawley, S. A. (2001) · BioEssays · doi:10.1002/bies.10009 · Cited by 784 · see citing works
Marti, H. J. H., Bernaudin, M., Bellail, A., Schoch, H., Euler, M., Petit, E., & Risau, W. (2000) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)64964-4 · Cited by 680 · see citing works
Consequences of Brief Ischemia: Stunning, Preconditioning, and Their Clinical Implications
Kloner, R. A., & Jennings, R. B. (2001) · Circulation · doi:10.1161/hc4801.100038 · Cited by 635 · see citing works
Transcription Factor HIF-1 Is a Necessary Mediator of the Pasteur Effect in Mammalian Cells
Seagroves, T. N., Ryan, H. E., Lu, H., Wouters, B. G., Knapp, M., Thibault, P., Laderoute, K. R., & Johnson, R. S. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.10.3436-3444.2001 · Cited by 634 · see citing works
Tissue oxygen tension and brain sensitivity to hypoxia
Erecińska, M., & Silver, I. A. (2001) · Respiration Physiology · doi:10.1016/s0034-5687(01)00306-1 · Cited by 615 · see citing works
Expression of hypoxia-inducible factor 1? in brain tumors
Zagzag, D., Zhong, H., Scalzitti, J. M., Laughner, E., Simons, J. W., & Semenza, G. L. (2000) · Cancer · doi:10.1002/1097-0142(20000601)88:11 · Cited by 603 · see citing works
Carling, D., Zammit, V. A., & Hardie, D. G. (1987) · FEBS Letters · doi:10.1016/0014-5793(87)80292-2 · Cited by 599 · see citing works
Cellular Mechanism of Oxygen Sensing
López‐Barneo, J., Pardal, R., & Ortega‐Sáenz, P. (2001) · Annual Review of Physiology · doi:10.1146/annurev.physiol.63.1.259 · Cited by 546 · see citing works
Dealing with energy demand: the AMP-activated protein kinase
Kemp, B. E., Mitchelhill, K. I., Stapleton, D., Michell, B. J., Chen, Z., & Witters, L. A. (1999) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(98)01340-1 · Cited by 521 · see citing works
Mechanisms of cell survival in hypoxia and hypothermia
Boutilier, R. G. (2001) · Journal of Experimental Biology · doi:10.1242/jeb.204.18.3171 · Cited by 519 · see citing works
Bolli, R., Jeroudi, M. O., Patel, B. S., DuBose, C. M., Lai, E. K., Roberts, R., & McCay, P. B. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.12.4695 · Cited by 469 · see citing works
Arsham, A. M., Howell, J. J., & Simon, M. C. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212770200 · Cited by 463 · see citing works
Direct role for potassium channel inhibition in hypoxic pulmonary vasoconstriction
Post, J. M., Hume, J. R., Archer, S. L., et al. (1992) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1992.262.4.c882 · Cited by 452 · see citing works
Role of fructose 2,6-bisphosphate in the control of glycolysis in mammalian tissues
Hue, L., & Rider, M. H. (1987) · Biochemical Journal · doi:10.1042/bj2450313 · Cited by 421 · see citing works
Minchenko, О. H., Leshchinsky, I., Opentanova, I., Sang, N., Srinivas, V., Armstead, V. E., & Caro, J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m110978200 · Cited by 370 · see citing works
ARNT-Deficient Mice and Placental Differentiation
Kozak, K. R., Abbott, B., & Hankinson, O. (1997) · Developmental Biology · doi:10.1006/dbio.1997.8758 · Cited by 328 · see citing works
Mottet, D., Dumont, V., Deccache, Y., Demazy, C., Ninane, N., Raes, M. J., & Michiels, C. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300763200 · Cited by 316 · see citing works
Self-citationLang, K. J. D., Kappel, A., & Goodall, G. J. (2002) · Molecular Biology of the Cell · doi:10.1091/mbc.02-02-0017 · Cited by 314 · see citing works
Hypoxia-inducible Factor and Its Biomedical Relevance
Huang, E. L., & Bunn, H. F. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.r200030200 · Cited by 313 · see citing works
Gnaiger, E. (2001) · Respiration Physiology · doi:10.1016/s0034-5687(01)00307-3 · Cited by 280 · see citing works
Hypoxia modulated gene expression: angiogenesis, metastasis and therapeutic exploitation
Dachs, G. U., & Tozer, G. M. (2000) · European Journal of Cancer · doi:10.1016/s0959-8049(00)00159-3 · Cited by 272 · see citing works
Hoskin, P., Sibtain, A., Daley, F. M., & Wilson, G. D. (2003) · British Journal of Cancer · doi:10.1038/sj.bjc.6601260 · Cited by 217 · see citing works
Carbonic anhydrase 9 as an endogenous marker for hypoxic cells in cervical cancer.
Olive, P. L., Aquino‐Parsons, C., MacPhail, S. H., Liao, S. Y., Raleigh, J. A., Lerman, M. I., & Stanbridge, E. J. (2001) · PubMed · Cited by 208 · see citing works
Fu, X., Wang, D., Nurse, C. A., Dinauer, M. C., & Cutz, E. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.8.4374 · Cited by 192 · see citing works
Detection of hypoxia in human squamous cell carcinoma by EF5 binding.
Evans, S. M., Hahn, S. M., Pook, D. R., Jenkins, W. T., Chalian, A. A., Zhang, P. J., Stevens, C., Weber, R. S., Weinstein, G. S., Benjamin, I., et al. (2000) · PubMed · Cited by 190 · see citing works
Adenylate as a Metabolic Regulator
Ramaiah, A., Hathaway, J. A., & Atkinson, D. (1964) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)91181-6 · Cited by 189 · see citing works
Heusch, G. (1998) · Physiological Reviews · doi:10.1152/physrev.1998.78.4.1055 · Cited by 182 · see citing works
Transduction pathways involved in Hypoxia-Inducible Factor-1 phosphorylation and activation
Minet, E., Michel, G., Mottet, D., Raes, M. J., & Michiels, C. (2001) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(01)00657-8 · Cited by 179 · see citing works
Self-citationSurviving hypoxia without really dying
Boutilier, R. G., & St‐Pierre, J. (2000) · Comparative Biochemistry and Physiology Part A Molecular & Integrative Physiology · doi:10.1016/s1095-6433(00)00234-8 · Cited by 160 · see citing works
Oxygen-regulated transcription factors and their role in pulmonary disease
Semenza, G. L. (2000) · Respiratory Research · doi:10.1186/rr27 · Cited by 160 · see citing works
Hibernation during Hypoxia in Cardiomyocytes
Budinger, G. R. S., Duranteau, J., Chandel, N. S., & Schumacker, P. T. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.6.3320 · Cited by 153 · see citing works
Contrasting effects of hypoxia on tension in rat pulmonary and mesenteric arteries
Yuan, X. J., Tod, M. L., Rubin, L. J., et al. (1990) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1990.259.2.h281 · Cited by 134 · see citing works
Shiritova, L. A., W, E. K., R, H. L., & M, E. (2002) · Advances in experimental medicine and biology · doi:10.1007/0-306-46825-5_21 · Cited by 128 · see citing works
Dart, C., & Standen, N. B. (1995) · The Journal of Physiology · doi:10.1113/jphysiol.1995.sp020565 · Cited by 125 · see citing works
Janssen, H. L., Haustermans, K. M., Sprong, D., Blommestijn, G. J. F., Hofland, I., Hoebers, F. J. P., Blijweert, E., Raleigh, J. A., Semenza, G. L., Varia, M. A., et al. (2002) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/s0360-3016(02)03935-4 · Cited by 117 · see citing works
Cellular responses to hypoxia after renal segmental infarction
Rosenberger, C., Griethe, W., Gruber, G., et al. (2003) · Kidney International · doi:10.1046/j.1523-1755.2003.00159.x · Cited by 115 · see citing works
Borutaitė, V., Mildažienė, V., Brown, G. C., & Brand, M. D. (1995) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/0925-4439(95)00080-1 · Cited by 96 · see citing works
Acute oxygen sensing: diverse but convergent mechanisms in airway and arterial chemoreceptors
Peers, C., & Kemp, P. J. (2001) · Respiratory Research · doi:10.1186/rr51 · Cited by 91 · see citing works
Hypoxia-inducible factor-1alpha is an intrinsic marker for hypoxia in cervical cancer xenografts.
Vukovic, V. M., Haugland, H. K., Nicklee, T., Morrison, A. J., & Hedley, D. W. (2001) · PubMed · Cited by 91 · see citing works
BIAGAS, K. V. (1999) · Current Opinion in Pediatrics · doi:10.1097/00008480-199906000-00009 · Cited by 80 · see citing works
Airway Chemotransduction: From Oxygen Sensor to Cellular Effector
Kemp, P. J., Lewis, A., Hartness, M. E., Searle, G. J., Miller, P., O'Kelly, I., & Peers, C. (2002) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.2206009 · Cited by 75 · see citing works
O2 Sensing by Airway Chemoreceptor-derived Cells
Kelly, A. M., Lewis, A., Peers, C., et al. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.11.7684 · Cited by 74 · see citing works
Cellular mechanisms of oxygen sensing at the carotid body: heme proteins and ion channels
Prabhakar, N. R., & Overholt, J. L. (2000) · Respiration Physiology · doi:10.1016/s0034-5687(00)00160-2 · Cited by 66 · see citing works
Vordermark, D., & Brown, J. M. (2003) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/s0360-3016(03)00289-x · Cited by 63 · see citing works
Metabolic control: A new solution to an old problem
Hardie, D. G. (2000) · Current Biology · doi:10.1016/s0960-9822(00)00744-2 · Cited by 51 · see citing works
Collingridge, D. R., & Rockwell, S. (2000) · International Journal of Cancer · doi:10.1002/1097-0215(20001020)90:5 · Cited by 37 · see citing works
Tinton, S. A., Tran‐Nguyen, Q., & Calderón, P. B. (1997) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1997.t01-1-00121.x · Cited by 17 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- O'Kelly I, Lewis A, Peers C, Kemp PJ: O(2) sensing by airway che- moreceptor-derived cells: protein kinase c activation reveals func- tional evidence for involvement of NADPH oxidase. J Biol Chem 2000, 275:7684 -7692
- Dewhirst MW, Klitzman B, Braun RD, Brizel DM, Haroon ZA, Secomb TW: Review of methods used to study oxygen transport at the micro- circulatory level. Int J Cancer 2000, 90:237-255
Cited by
Sorted by citations
Baliyan, S., Mukherjee, R., Priyadarshini, A., Vibhuti, A., Gupta, A., Pandey, R. P., & Chang, C.-M. (2022) · Molecules · doi:10.3390/molecules27041326 · Cited by 1,485 · see citing works
Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes
Hamanaka, R. B., & Chandel, N. S. (2010) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2010.04.002 · Cited by 1,011 · see citing works
Hesp, A. C., Schaub, J. A., Prasad, P. V., Vallon, V., Laverman, G. D., Bjornstad, P., & van Raalte, D. H. (2020) · Kidney International · doi:10.1016/j.kint.2020.02.041 · Cited by 202 · see citing works
Short-term physiological hypoxia potentiates the therapeutic function of mesenchymal stem cells
Antebi, B., Rodriguez, L. A., Walker, K. P., Asher, A. M., Kamucheka, R. M., Alvarado, L., Mohammadipoor, A., & Cancio, L. C. (2018) · Stem Cell Research & Therapy · doi:10.1186/s13287-018-1007-x · Cited by 137 · see citing works
Activation of AMPK under Hypoxia: Many Roads Leading to Rome
Dengler, F. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21072428 · Cited by 133 · see citing works
Hypoxia inducible factor 1α regulates T cell receptor signal transduction
Neumann, A. K., Yang, J., Biju, M. P., Joseph, S. K., Johnson, R. S., Haase, V. H., Freedman, B. D., & Turka, L. A. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506070102 · Cited by 120 · see citing works
Gusarova, G. A., Dada, L. A., Kelly, A. M., Brodie, C., Witters, L. A., Chandel, N. S., & Sznajder, J. I. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.00054-09 · Cited by 118 · see citing works
Oxygen Regulation in Development: Lessons from Embryogenesis towards Tissue Engineering
Fathollahipour, S., Patil, P. S., & Leipzig, N. D. (2018) · Cells Tissues Organs · doi:10.1159/000493162 · Cited by 101 · see citing works
Regulation of alveolar epithelial function by hypoxia
Zhou, G., Dada, L. A., & Sznajder, J. I. (2008) · European Respiratory Journal · doi:10.1183/09031936.00155507 · Cited by 57 · see citing works
Koens, R., Tabata, Y., Serrano, J. C., Aratake, S., Yoshino, D., Kamm, R. D., & Funamoto, K. (2020) · APL Bioengineering · doi:10.1063/1.5127069 · Cited by 53 · see citing works
Herrera-Campos, A. B., Zamudio-Martinez, E., Delgado-Bellido, D., Fernández-Cortés, M., Montuenga, L. M., Oliver, F. J., & Garcia-Diaz, A. (2022) · Cancers · doi:10.3390/cancers14112740 · Cited by 17 · see citing works
- Authors
- Michiels, C.
- Affiliations
- University of Namur (BE)
- Corresponding author
- Michiels, Carine
- ORCID
- Michiels, Carine
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2004-06
- Volume
- 164
- Issue
- 6
- Pages
- 1875-1882
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC1615763
- OpenAlex
- W1998761071
- Cited by
- 559
- References
- 62
- Citations by year
- 2026: 11 · 2025: 37 · 2024: 44 · 2023: 41 · 2022: 49 · 2021: 48 · 2020: 47 · 2019: 41 · 2018: 45 · 2017: 30 · 2016: 20 · 2015: 21 · 2014: 17 · 2013: 20 · 2012: 5
- FWCI
- 0.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Repository of the University of Namur (publishedVersion, other-oa)
- Digital Access to Libraries (Université catholique de Louvain (UCL), l'Université de Namur (UNamur) and the Université Saint-Louis (USL-B)) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › High Altitude and Hypoxia
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Keywords
- hypoxia, hypoxia adaptation, oxygen sensing, oxygen availability, myocardial ischemia, cerebral ischemia, carcinogenesis, myocardial infarction, stroke, cancer, prolonged hypoxia
- MeSH terms
- Acclimatization, Animals, Hypoxia, Humans, Mitochondria, Oxidation-Reduction, Oxygen, Oxygen Consumption
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