The expression of hypoxia-inducible factor HIF1α as a criterion for the development of tissue hypoxia

The aim of the study was to evaluate the suitability of the use of the expression level of hypoxia-inducible factor HIF1α to diagnose the severity of tissue hypoxia. Expression HIF1α is a typical response of the genome of the cells in the hypoxic effects, triggering multidimensional mechanisms of adaptation to hypoxia, and improve the ability of tissues to experience adverse effects. Experimental hypoxia was created by the rise of laboratory Wistar rats in the chamber at a height of 6, 8, 10, 11 and 12 km. Duration of exposure varied from 30 to 5 minutes depending on altitude. Immediately after the descent of animals climbed the biological materials (whole blood, kidney, liver, heart, brain), in which method the real-time PCR determined the expression of HIF1a. As the standardization gene used was the gene "household" TSPO. It is shown that HIF1a, and TSPO have pronounced tissue-specific. Under hypoxic conditions the expression of TSPO elevation is characterized by high variability. Dynamics of expression of HIF1a elevation shows the possibility of using this indicator to assess the severity of tissue hypoxia-independent method of modeling hypoxic exposure.

гипоксия, гипоксия-индуцибельный фактор, лабораторные животные, экспрессия, HIF1α, ПЦР в реальном времени, hypoxia, hypoxia-inducible factor, laboratory animals, expression of HIF1a, real-time PCR

1. Малышев И.Ю. Стресс-белки в биологии и медицине. - М.: ГЕОТАР-Медиа, 2012. - 176 с.

2. Bianchi L., Tacchini L., Cairo G. HIF-1-mediated activation of transferrin receptor gene transcription by iron chelation // Nucleic Acids Res., 1999; 27: 4223-4227.

3. Chen J., Zhao S., Nakada K., Kuge Y., Tamaki N., Okada F., Wang J., Shindo M., Higashino F., Takeda K. Dominant-negative hypoxia-inducible factor-1 alpha reduces tumorigenicity of pancreatic cancer cells through the suppression of glucose metabolism // Am. J. Pathol., 2003; 162: 1283-1291.

4. Conway E.M., Collen D., Carmeliet P. Molecular mechanisms of blood vessel growth // Cardiovasc. Res., 2001; 49: 507-521.

5. Eckhart A.D., Yang N., Xin X., Faber J.E. Characterization of the alpha1B-adrenergic receptor gene promoter region and hypoxia regulatory elements in vascular smooth muscle // Proc. Natl Acad. Sci. USA, 1997; 94: 9487-9492.

6. Feldser D., Agani F., Lyer N.V., Pak B., Ferreira G., Semenza G.L. Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2 // Cancer. Res., 1999; 59: 3915-3918.

7. Fukuda R., Zhang H., Kim J.W., Shimoda L., Dang C.V., Semenza G.L. HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells // Cell, 2007; 129: 111-122.

8. Gordan J.D., Thompson C.B., Simon M.C. HIF and c-Myc: Sibling rivals for control of cancer cell metabolism and proliferation // Cancer. Cell, 2007; 12: 108-113.

9. Hu J., Discher D.J., Bishopric N.H., Webster K.A. Hypoxia regulates expression of the endothelin-1 gene through a proximal hypoxia-inducible factor-1 binding site on the antisense -strand // Biochem. Biophys. Re.s Commun., 1998; 245: 894-899.

10. Kim J.W., Tchernyshyov I., Semenza G.L., Dang C.V. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia // Cell Metab, 2006; 3: 177-185.

11. Krishnamachary B., Berg-Dixon S., Kelly B., Agani F., Feldser D., Ferreira G., Iyer N., LaRusch J., Pak B., Taghavi P. Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1 // Cancer Res 2003. 63:1138-1143.

12. Lee P.J., Jiang B.H., Chin B.Y., Iyer N.V., Alam J., Semenza G.L., Choi A.M. Hypoxia-inducible factor-1 mediates transcriptional activation of the hemeoxygenase-1 gene in response to hypoxia // J. Biol. Chem., 1997; 272: 5375-5381.

13. Lok C.N., Ponka P. Identification of a hypoxia response element in the transferrin receptor gene // J. Biol. Chem., 1999; 274: 24147-24152.

14. Lu H., Forbes R.A., Verma A. Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis // J. Biol. Chem., 2002; 277: 23111-23115.

15. Makino Y., Cao R., Svensson K., Bertilsson G., Asman M., Tanaka H. Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression // Nature, 2001; 414: 550-554.

16. Melillo G., Musso T., Sica A., Taylor L.S., Cox G.W., Varesio L. A hypoxiaresponsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promoter // J. Exp. Med., 1995; 182: 1683-1693.

17. Mukhopadhyay C.K., Mazumder B., Fox P.L. Role of hypoxia-inducible factor-1 in transcriptional activation of ceruloplasmin by iron deficiency // J. Biol. Chem. 2000; 275: 21048-21054.

18. Neufeld G., Cohen T., Gengrinovitch S., Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors // FASEB J., 1999; 13: 9-22.

19. Nguyen S.V., Claycomb W.C. Hypoxia regulates the expression of the adrenomedullin and HIF-1 genes in cultured HL-1 cardiomyocytes // Biochem. Biophys. Res. Commun., 1999; 265: 382-386.

20. Papandreou I., Cairns R.A., Fontana L., Lim A.L., Denko N.C. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption // Cell Metab., 2006; 3: 187-197.

21. Rolfs A., Kvietikova I., Gassmann M., Wenger R.H. Oxygen-regulated transferrin expression is mediated by hypoxia-inducible factor-1 // J. Biol. Chem., 1997; 272: 20055-20062.

22. Semenza G.L., Nejfelt M.K., Chi S.M., Antonarakis S.E. Hypoxia-inducible nuclear factors bind to an enhancer element located 3 to the human erythropoietin gene // Proc. Natl Acad. Sci. USA, 1991; 88: 5680-5684.

23. Semenza G.L., Jiang B.H., Leung S.W., Passantino R., Concordet J.P., Maire P., Giallongo A. Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1 // J. Biol. Chem., 1996; 271: 32529-32537.

24. Semenza G.L. Targeting HIF-1 for cancer therapy // Nat. Rev. Cancer., 2003; 3: 721-732.

25. 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 // FASEB J., 2001. V. 15. N. 11. P. 2445-2453.

26. Tacchini L., Radice L., Bernelli-Zazzera A. Differential activation of some transcription factors during rat liver ischemia, reperfusion, and heat shock // J. Cell Physiol., 1999; 180: 255-262.

27. Wang G.L., Semenza G.L. Purification and characterization of hypoxia-inducible factor 1 // J. Biol. Chem., 1995; 270: 1230-1237.