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,12,1,
* Liver Laboratories, University of Birmingham, Birmingham, UK;
Institutes of Physiology, University of Zürich, Zürich, Switzerland; and
Medical University Lübeck, Lübeck, Germany
2Correspondence: Liver Laboratories, Clinical Research Block, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK. E-mail: d.m.stroka{at}bham.ac.uk.
Adaptation to hypoxia is regulated by hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor consisting of an oxygen-regulated 
subunit and a constitutively expressed ß subunit. Although HIF-1 is regulated mainly by oxygen tension through the oxygen-dependent degradation of its subunit, in vitro it can also be modulated by cytokines, hormones and genetic alterations. To investigate HIF-1 activation in vivo, we determined the spatial and temporal distribution of HIF-1 in healthy mice subjected to varying fractions of inspiratory oxygen. Immunohistochemical examination of brain, kidney, liver, heart, and skeletal muscle revealed that HIF-1 is present in mice kept under normoxic conditions and is further increased in response to systemic hypoxia. Moreover, immunoblot analysis showed that the kinetics of HIF-1 expression varies among different organs. In liver and kidney, HIF-1 reaches maximal levels after 1 h and gradually decreases to baseline levels after 4 h of continuous hypoxia. In the brain, however, HIF-1 is maximally expressed after 5 h and declines to basal levels by 12 h. Whereas HIF-1ß is constitutively expressed in brain and kidney nuclear extracts, its hepatic expression increases concomitantly with HIF-1. Overall, HIF-1 expression in normoxic mice suggests that HIF-1 has an important role in tissue homeostasis.—Stroka, D. M., Burkhardt, T., Desbaillets, I., Wenger, R. H., Neil, D. A. H., Bauer, C., Gassmann, M., Candinas, D. HIF-1 is expressed in normoxic tissue and displays an organ specific regulation under systemic hypoxia.
Key Words: hypoxia-inducible factor 1 • ARNT • tissue hypoxia
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 P. Maxwell HIF-1: An Oxygen Response System with Special Relevance to the Kidney J. Am. Soc. Nephrol., November 1, 2003; 14(11): 2712 - 2722. [Full Text] [PDF]
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P. B. Freeburg and D. R. Abrahamson Hypoxia-Inducible Factors and Kidney Vascular Development J. Am. Soc. Nephrol., November 1, 2003; 14(11): 2723 - 2730. [Abstract] [Full Text] [PDF]
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Y. Cuevas, R. Hernandez-Alcoceba, J. Aragones, S. Naranjo-Suarez, M. C. Castellanos, M. A. Esteban, S. Martin-Puig, M. O. Landazuri, and L. del Peso Specific Oncolytic Effect of a New Hypoxia-Inducible Factor-Dependent Replicative Adenovirus on von Hippel-Lindau-Defective Renal Cell Carcinomas Cancer Res., October 15, 2003; 63(20): 6877 - 6884. [Abstract] [Full Text] [PDF]
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R. M. Crawford, S. Jovanovic, G. R. Budas, A. M. Davies, H. Lad, R. H. Wenger, K. A. Robertson, D. J. Roy, H. J. Ranki, and A. Jovanovic Chronic Mild Hypoxia Protects Heart-derived H9c2 Cells against Acute Hypoxia/Reoxygenation by Regulating Expression of the SUR2A Subunit of the ATP-sensitive K+ Channel J. Biol. Chem., August 15, 2003; 278(33): 31444 - 31455. [Abstract] [Full Text] [PDF]
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 Z. Cai, D. J. Manalo, G. Wei, E. R. Rodriguez, K. Fox-Talbot, H. Lu, J. L. Zweier, and G. L. Semenza Hearts From Rodents Exposed to Intermittent Hypoxia or Erythropoietin Are Protected Against Ischemia-Reperfusion Injury Circulation, July 8, 2003; 108(1): 79 - 85. [Abstract] [Full Text] [PDF]
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 T. N. Seagroves, D. Hadsell, J. McManaman, C. Palmer, D. Liao, W. McNulty, B. Welm, K.-U. Wagner, M. Neville, and R. S. Johnson HIF1{alpha} is a critical regulator of secretory differentiation and activation, but not vascular expansion, in the mouse mammary gland Development, April 15, 2003; 130(8): 1713 - 1724. [Abstract] [Full Text] [PDF]
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P. B. Freeburg, B. Robert, P. L. St. John, and D. R. Abrahamson Podocyte Expression of Hypoxia-Inducible Factor (HIF)-1 and HIF-2 during Glomerular Development J. Am. Soc. Nephrol., April 1, 2003; 14(4): 927 - 938. [Abstract] [Full Text] [PDF]
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S. Kaluz, M. Kaluzova, and E. J. Stanbridge Expression of the Hypoxia Marker Carbonic Anhydrase IX Is Critically Dependent on SP1 Activity. Identification of a Novel Type of Hypoxia-responsive Enhancer Cancer Res., March 1, 2003; 63(5): 917 - 922. [Abstract] [Full Text] [PDF]
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T. Daikoku, H. Matsumoto, R. A. Gupta, S. K. Das, M. Gassmann, R. N. DuBois, and S. K. Dey Expression of Hypoxia-inducible Factors in the Peri-implantation Mouse Uterus Is Regulated in a Cell-specific and Ovarian Steroid Hormone-dependent Manner. EVIDENCE FOR DIFFERENTIAL FUNCTION OF HIFs DURING EARLY PREGNANCY J. Biol. Chem., February 21, 2003; 278(9): 7683 - 7691. [Abstract] [Full Text] [PDF]
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J. Zhou, J. Fandrey, J. Schumann, G. Tiegs, and B. Brune NO and TNF-alpha released from activated macrophages stabilize HIF-1alpha in resting tubular LLC-PK1 cells Am J Physiol Cell Physiol, February 1, 2003; 284(2): C439 - C446. [Abstract] [Full Text] [PDF]
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C. Madjdpour, U. R. Jewell, S. Kneller, U. Ziegler, R. Schwendener, C. Booy, L. Klausli, T. Pasch, R. C. Schimmer, and B. Beck-Schimmer Decreased alveolar oxygen induces lung inflammation Am J Physiol Lung Cell Mol Physiol, February 1, 2003; 284(2): L360 - L367. [Abstract] [Full Text] [PDF]
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 H. J. Schoch, S. Fischer, and H. H. Marti Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain Brain, November 1, 2002; 125(11): 2549 - 2557. [Abstract] [Full Text] [PDF]
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M. R. Mehrabi, N. Serbecic, F. Tamaddon, C. Kaun, K. Huber, R. Pacher, T. Wild, G. Mall, J. Wojta, and H.-D Glogar Clinical and experimental evidence of prostaglandin E1-induced angiogenesis in the myocardium of patients with ischemic heart disease Cardiovasc Res, November 1, 2002; 56(2): 214 - 224. [Abstract] [Full Text] [PDF]
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 S. Jesmin, I. Sakuma, Y. Hattori, and A. Kitabatake In Vivo Estrogen Manipulations on Coronary Capillary Network and Angiogenic Molecule Expression in Middle-Aged Female Rats Arterioscler. Thromb. Vasc. Biol., October 1, 2002; 22(10): 1591 - 1597. [Abstract] [Full Text] [PDF]
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 R. H. WENGER Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression FASEB J, August 1, 2002; 16(10): 1151 - 1162. [Abstract] [Full Text] [PDF]
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H. Lu, R. A. Forbes, and A. Verma Hypoxia-inducible Factor 1 Activation by Aerobic Glycolysis Implicates the Warburg Effect in Carcinogenesis J. Biol. Chem., June 21, 2002; 277(26): 23111 - 23115. [Abstract] [Full Text] [PDF]
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G. Hopfl, R. H. Wenger, U. Ziegler, T. Stallmach, O. Gardelle, R. Achermann, M. Wergin, B. Kaser-Hotz, H. M. Saunders, K. J. Williams, et al. Rescue of Hypoxia-inducible Factor-1{alpha}-deficient Tumor Growth by Wild-Type Cells Is Independent of Vascular Endothelial Growth Factor Cancer Res., May 1, 2002; 62(10): 2962 - 2970. [Abstract] [Full Text] [PDF]
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D. CHILOV, T. HOFER, C. BAUER, R. H. WENGER, and M. GASSMANN Hypoxia affects expression of circadian genes PER1 and CLOCK in mouse brain FASEB J, December 1, 2001; 15(14): 2613 - 2622. [Abstract] [Full Text] [PDF]
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