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ISSN 2522-9028 (Print)
ISSN 2522-9036 (Online)

Fiziologichnyi Zhurnal

is a scientific journal issued by the

Bogomoletz Institute of Physiology
National Academy of Sciences of Ukraine

Editor-in-chief: V.F. Sagach

The journal was founded in 1955 as
1955 – 1977 "Fiziolohichnyi zhurnal" (ISSN 0015 – 3311)
1978 – 1993 "Fiziologicheskii zhurnal" (ISSN 0201 – 8489)
1994 – 2016 "Fiziolohichnyi zhurnal" (ISSN 0201 – 8489)
2017 – "Fiziolohichnyi zhurnal" (ISSN 2522-9028)

Fiziol. Zh. 2013; 59(6): 98-110

Phenotypic characteristics of factor expression induced by hypoxia and redox status of the rat neocortical cells at different stages of adaptation to hypoxia

Kirova IuI, Germanova ÉL, Luk'ianova LD

    Institute of General Pathology and Pathophysiology, Russian Academia Medical Sciences, Russia


Hypoxic preconditioning induces two-phase increase of HIF-1alpha expression in the neocortex of low-resistance rats. The first, brief phase appears after each hypoxic episode and rapidly disappears in normoxic conditions. The second increase in of HIF-1alpha expression occurs in 24 hours after the hypoxic episode. The phase-nature of HIF-1alpha expression corresponds to the dynamics of urgent and long-term resistance in low-resistance rats, which suggests the HIF-1alpha involvement in mechanisms of urgent and long-term adaptation. It was found that in the mode of preconditioning, hypoxic treatments mobilized the anti-oxidant system (activated Cu, Zn-SOD) and had no effect on the intensity of lipid peroxidation processes in neocortex (INH, 10% O2) or even decreased the content of lipid peroxidation products and oxidized glutathione in neocortical cells in the early post-hypoxic period (HBH-5000, 10.5% O2). Thus, ROS do not play a key role in the induction of HIF-1alpha expression and fast-response/long-term adaptation to O2 deficiency in hypoxia-sensitive animals. In high-resistance rats, hypoxia preconditioning does not influence the HIF-1alpha protein expression and the adaptation. Severe hypoxic modes (HBH-7000, 8% O2) caused activation of lipid peroxidation processes in neocortex of hypoxia-sensitive rats. With the pro-oxidant systems dominating over the anti-oxidant ones, the neocortical expression of HIF-1alpha was found to decrease, which was accompanied by the impairment of the mechanisms of fast-response/long-term adaptation to hypoxia.

Keywords: HIF-1a, neocortex, preconditioning hypoxia,severe hypoxia, high-resistance rats, low-resistance rats, urgentand long-term adaptation to hypoxia, lipid peroxidation, lipidhydroperoxides, conjugated dienes, thiobarbituric acid reactivesubstances, oxidized glutathione


  1. Kirova Yu.I., Germanova E.L., Luk'yanova L.D. Fenotipicheskie osobennosti dinamiki soderzhaniya HIF-1av neokortekse kris pri razlichnih rezhimah gipoksii. Byul. eksperim. biologii i meditsini. 2012. 154,N 12. P. 681-686.
  3. Luk'yanova L.D. Sovremennie problemi adaptatsii kgipoksii. Signal'nie mehanizmi i ih rol' v sistemnoi regulyatsii . Patol. fiziologiya i eksperim.terapiya. 2011. N 1. P. 3-19.
  5. Luk'yanova L.D., Germanova E.L., Kopaladze R.A. Zakonomernosti formirovaniya rezistentnosti organizmapri raznih rezhimah gipoksicheskogo prekonditsionirovaniya: rol' gipoksicheskogo perioda i reoksigenatsii . Byul. eksperim. biologii i meditsini. 2009. 147, N 4. P. 380-384.
  7. Luk'yanova L.D., Dudchenko A.M. Triggernaya rol'energeticheskogo obmena v kaskade funktsional'no-metabolicheskih narushenii pri gipoksii. V kn.:Problemi gipoksii: molekulyarnie, fiziologicheskiei meditsinskie aspekti . Pod. red. Luk'yanovoi L.D.,Ushakova I.B. M.: Istoki, 2004. P. 51-84.
  9. Luk'yanova L.D., Kirova Yu.I. Vliyanie gipoksicheskogo prekonditsionirovaniya na svobodnoradikal'nieprotsessi v tkanyah kris s razlichnoi tolerantnost'yuk gipoksii . Byul. eksperim. biologii i meditsini. 2011. 151, N 3. P. 292-296.
  11. Luk'yanova L.D., Kirova Yu.I., Sukoyan G.V. Signal'nie mehanizmi adaptatsii k gipoksii i ih rol' vsistemnoi regulyatsii . Biol. membrani. 2012. 29,N 4. P. 238-252.
  13. Chernobaeva G.N., Luk'yanova L.D. Rol' individual'noi rezistentnosti k gipoksicheskomu faktoru pripoiske antigipoksantov i otsenke effektivnosti ihdeistviyayu V kn.: Farmakologicheskaya korrektsiyagipoksicheskih sostoyanii. M., 1989. P. 160-164.
  15. Abramov A.Y., Scorziello A., Duchen M.R. Three distinctmechanisms generate oxygen free radicals in neurons andcontribute to cell death during anoxia and reoxygenation. J. Neurosci. 2007. 27, N 5. P. 1129-1138. CrossRef PubMed
  17. Althausen S., Mengesdorf T., Mies G. Changes in thephosphorylation of initiation factor eIF-2alpha, elongationfactor eEF-2 and p70 S6 kinase after transient focalcerebral ischaemia in mice . J. Neurochem. 2001. N 78. P. 779-787. CrossRef PubMed
  19. Bell E.L., Klimova T.A., Eisenbart J., Moraes C.T., MurphyM.P., Budinger G.R., Chandel N.S. The Qo site of the mitochondrialcomplex III is required for the transduction ofhypoxic signaling via reactive oxygen species production. J. Cell Biol. 2007. N 177. P. 1029-1036. CrossRef PubMed PubMedCentral
  21. Boveris A., Chance B. The mitochondrial generation ofhydrogen peroxide. General properties and effect of hyperbaricoxygen . Biochem. J. 1973. N 134. P. 707-716. CrossRef PubMed PubMedCentral
  23. Bruick R.K. O2 sensing in the hypoxic response pathway:regulation of the hypoxia-inducible transcription factor. Genes & Development. 2003. N 17. P. 2614-2623. CrossRef PubMed
  25. Calvert J.W., Cahill J., Yamaguchi-Okada M., Zhang JH.Oxygen treatment after experimental hypoxia-ischemiain neonatal rats alters the expression of HIF-1a and itsdownstream target genes . J. Appl. Physiol. 2006. N 101. P. 853-865. CrossRef PubMed
  27. Dringen R., Gutterer J.M. Glutathione reductase frombovine brain . Methods Enzymol. 2002. N 348. P. 281-288. CrossRef  
  28. Esterbauer H., Striegl G., Puhl H., Rotheneder M. Continuousmonitoring of in vitro oxidation of human lowdensity lipoprotein . Free Radic. Res. Commun. 1989. N 6. P. 67-75. CrossRef PubMed
  30. Eyer P., Podhradsky D. Evaluation of the micromethodfor determination of glutathione using enzymatic cyclingand Ellman's reagent . Anal. Biochem. 1986. N 153. P. 57-66. CrossRef  
  31. Griendling K.K., Sorescu D., Lassegue B., Ushio-FukaiM. Modulation of protein kinase activity and gene expressionby reactive oxygen species and their role in vascularphysiology and Pathophysiology . Arterioscler. Thromb.Vasc. Biol. 2000. N 20. P. 2175-2183. CrossRef PubMed
  33. Haddad J.J. Antioxidant and prooxidant mechanisms inthe regulation of redox(y)-sensitive transcription factors. Cell Signal. 2002. N 14. P. 879-897. CrossRef  
  34. Haddad J.J., Land S.C. O2-evoked regulation of HIF-1 andNF-B in perinatal lung epithelium requires glutathionebiosynthesis . Amer. J. Physiol. Lung. Cell Mol Physiol. 2000. N 278. P. L492-L503. CrossRef PubMed
  36. Haddad J.J., Olver R.E., Land S.C. Antioxidant. prooxidantequilibrium regulates HIF-1 alpha and NF-kappa Bredox sensitivity evidence for inhibition by glutathioneoxidation in alveolar epithelial cells . J. Biol. Chem. 2000. N 275. P. 21130-21139. CrossRef PubMed
  38. Hermes-Lima M., Willmore W.G., Storey K.B. Quantificationof lipid peroxidation in tissue extracts based on Fe(III)xylenol orange complex formation . Free Radical Biology& Medicine. 1995. 19, N 3. P. 271-280. CrossRef  
  39. Kaelin W.G., Ratcliffe P.J. Oxygen sensing by metazoans:the central role of the HIF hydroxylase pathway . Mol.Cell. 2008. N 30. P.393-402. CrossRef PubMed
  41. Katschinski D.M., Le L., Schindler S.G., Thomas T.,Voss A.K., Wenger R.H. Interaction of the PAS B domainwith HSP90 accelerates hypoxia-inducible factor-1 alphastabilization . Cell Physiol. Biochem. 2004. N 14. P. 351-360. CrossRef PubMed
  43. Lukyanova L.D., Dudchenko A.M., Tsybina T.A., GermanovaE.L., Tkatchuk E.N. Mitochondrial signalingin Adaptation to Hypoxia. In: Adaptation Biologyand Medicine . Eds Lukyanova L.D., Takeda N., SingalP.K. Publishing House New Dehli, India, 2008. 5. P. 245-260. PubMedCentral
  45. Lukyanova L.D., Germanova E.L., Kirova YuI. The SignalFunction of Succinate and Free Radicals in Mechanisms ofPreconditioning and Long-term Adaptation to Hypoxia. In: Adaptation Biology and Medicine . Eds Wang P., KuoC.-H., Takeda N., Singal P.K. Publishing House NewDehli, India, 2011. 6. P. 251-277. PubMedCentral
  47. Lukyanova L.D., Germanova E.L., Kirova J.I., LyskoA.I. The signal function of succinate and free radicals inmechanisms of preconditioning and long-term adaptationto hypoxia. In: Adaptation Biology and Medicine . EdsWang P., Kuo C.-H., Takeda N., Singal P.K. PublishingHouse New Dehli, India, 2009. 1. P. 45-48. PubMedCentral
  49. Maxwell P.H., Wiesener M.S., Chang G.W., Clifford S.C.,Vaux E.C., Cockman M.E., Wykoff C.C., Pugh C.W., MaherE.R., Ratcliffe P.J. The tumour suppressor protein VHLtargets hypoxia inducible factors for oxygen-dependentproteolysis . Nature. 1999. N 399. P. 271-275. CrossRef PubMed
  51. Okawa H., Ohishi N., Yagi K. Assay for lipid peroxidesin animal tissues by thiobarbituric acid reaction . Anal.Biochem. 1979. N 95. P. 351-358. CrossRef  
  52. Ozdemir G., Ozden M., Maral H., Kuskay S., CetinalpP., Tarkun I. Malondialdehyde, glutathione, glutathioneperoxidase and homocysteine levels in type 2 diabeticpatients with and without microalbuminuria . Ann. Clin.Biochem. 2005. N 42. P. 99-104. CrossRef PubMed
  54. Paky A., Michael J.R., Burke-Wolin T.M., Wolin M.S.,Gurtner G.H. Endogenous production of superoxide byrabbit lungs: effects of hypoxia or metabolic inhibitors. J. Appl. Physiol. 1993. N 74. P. 2868-2874. CrossRef PubMed
  56. Semenza G.L. Targeting HIF-1 for cancer therapy . Cancer. 2003. N 3. P. 721-732. PubMed
  58. Semenza G.L. Involvement of oxygen-sensing pathwaysin physiologic and pathologic erythropoiesis . Blood. 2009. 114, N 10. P. 2015-2019. CrossRef PubMed
  60. Selak M.A., Armour S.M., MacKenzie E.D., BoulahbelH., Watson D.G., Mansfeld K.D., Pan Y., Simon M.C.,Thompson C.B., Gottlieb E. Succinate links TCA cycledysfunction to oncogenesis by inhibiting HIF- prolylhydroxylase . Cancer Cell. 2005. N 7. P. 77-85. CrossRef PubMed
  62. Shringarpure R., Grune T., Mehlhase J., Davies K.J.Ubiquitin conjugation is not required for the degradationof oxidized proteins by proteasome . J. Biol. Chem. 2003. N 1. P. 311-318. CrossRef PubMed
  64. Stroka D.M., Burkhardt T., Desbaillets I. HIF-1 is expressedin normoxic tissue and displays an organ-specificregulation under systemic hypoxia . FASEB J. 2001. N 15. P. 2445-2453. CrossRef  
  65. Torres M., Forman H.J. Redox signaling and the MAPkinasepathways . Biofactors. 2003. N 17. P. 287-296. CrossRef PubMed
  67. Turrens J.F. Mitochondrial formation of reactive oxygenspecies . J. Physiol. 2003. N 15. P. 335-344. CrossRef PubMed PubMedCentral
  69. Tuttle S.W., Maity A., Oprysko P.R., Kachur A.V., AyeneI.S., Biaglow J.E., Koch C.J. Detection of reactive oxygenspecies via endogenous oxidative pentose phosphate cycleactivity in response to oxygen concentration . J. Biol.Chem. 2007. 282, N 51. P. 36790-36796. CrossRef PubMed
  71. Ukeda H., Maeda S., Ishii T., Sawamura M. Spectrophotometricassay for superoxide dismutase based ontetrazolium salt 3'--1--(phenylamino)-carbonyl--3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzenesulfonicacid hydrate reduction by xanthine-xanthine oxidase. Anal. Biochem. 1997. N 251. P. 206-209. CrossRef PubMed
  73. Vargas S.L., Toma I., Kang J.J., Meer E.J., Peti-PeterdiJ. Activation of the succinate receptor GPR91 in maculadensa cells causes renin release . J. Amer. Soc. Nephrol. 2009. N 20. P. 1002-1011. CrossRef PubMed PubMedCentral
  75. Wang G.L., Jiang B.H., Semenza G.L. Effect of alteredredox states on expression and DNA-binding activityof hypoxia-inducible factor . Biochem. Biophys. Res.Comm. 1995. N 2. P. 550-556. CrossRef PubMed
  77. Wang G.L., Jiang B.H., Rue E.A., Semenza G.L. Hypoxiainduciblefactor 1 is a basic-helix-loop-helix-PAS heterodimerregulated by cellular O2 tension . Proc. Natl. Acad.Sci. USA. 1995. N 92. P. 5510-5514. CrossRef PubMed

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