Chemoreception pp 171-178 | Cite as

Regulation of the Hypoxia-inducible Transcription Factor HIF-1 by Reactive Oxygen Species in Smooth Muscle Cells

  • Rachida Siham Bel Aiba
  • Agnes Görlach
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 536)


Hypoxia is able to activate the expression of a number of genes that are important for the cell to adapt to low oxygen conditions such as erythropoietin, vascular endothelial growth factor (VEGF) or plasminogen activator inhibitor-1 (PAI-1). The major transcription factor involved in the gene induction by hypoxia is the hypoxia-inducible factor-1 (HIF-1) (Semenza et al. 2001) which consists of two subunits, HIF-1 a and HIF-ß also known as ARNT. While the ARNT protein is readily found in the cell, the HIF-1 a protein is undetectable under normoxic conditions. In fact, under normal oxygen conditions, this protein is modified by prolyl and asparaginyl hydroxylation, ubiquitinylated and degradated by the proteasome. During hypoxia, hydroxylase activity is reduced, thus allowing HIF-1 a protein levels to increase (Kaelin, 2002). The HIF-1 a protein can then translocate to the nucleus, interact with the ARNT subunit, bind to specific DNA binding sites named hypoxia response elements (HRE) and finally induce transcription of the target genes.


Vascular Endothelial Growth Factor Hepatocyte Growth Factor NADPH Oxidase Hypoxia Response Element Human Vascular Smooth Muscle Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Babior, B.M., 1999, NADPH oxidase: an update. Blood 93: 1464–1476.PubMedGoogle Scholar
  2. Bassus, S., Herkert, O., Kronemann, N., Gorlach, A., Bremerich, D., Kirchmaier, C.M., Busse, R., Schini-Kerth, V.B., 2001, Thrombin causes vascular endothelial growth factor expression in vascular smooth muscle cells: role of reactive oxygen species. Arterioscler Thromb Vase Biol 21: 1550–1555.CrossRefGoogle Scholar
  3. Brandes, R.P., Viedt, C., Nguyen, K., Beer, S., Kreuzer, J., Busse, R., Gorlach, A., 2001, Thrombin-induced MCP-1 expression involves activation of the p22phox-containing NADPH oxidase in human vascular smooth muscle cells. Thromb Haemost 85: 1104–1110.PubMedGoogle Scholar
  4. Gorlach, A., Diebold, I., Schini-Kerth, V.B., Berchner-Pfannschmidt, U., Roth, U., Brandes, R.P., Kietzmann, T., Busse, R., 2001, Thrombin activates the hypoxia-inducible factor-1 signaling pathway in vascular smooth muscle cells: Role of the p22(phox)-containing NADPH oxidase. Circ Res 89: 47–54.PubMedCrossRefGoogle Scholar
  5. Gorlach, A., Kietzmann, T., Hess, J., 2002, Redox Signaling through NADPH Oxidases: Involvement in Vascular Proliferation and Coagulation. Ann N YAcad Sci 973: 505–507.CrossRefGoogle Scholar
  6. Griendling, K.K., Sorescu, D., Ushio-Fukai, M., 2000, NAD(P)H, oxidase: role in cardiovascular biology and disease. Cire Res 86: 494–501.CrossRefGoogle Scholar
  7. Hellwig-Burgel, T., Rutkowski, K., Metzen, E., Fandrey, J., Jelkmann, W., 1999, Interleukin-lbeta and tumor necrosis factor-alpha stimulate DNA binding of hypoxia-inducible factor-1. Blood 94 : 1561–1567.PubMedGoogle Scholar
  8. Herkert, O., Diebold, I., Brandes, R.P., Hess, J., Busse, R., Gorlach, A., 2002, NADPH oxidase mediates tissue factor-dependent surface procoagulant activity by thrombin in human vascular smooth muscle cells. Circulation 105: 2030–2036.PubMedCrossRefGoogle Scholar
  9. Kaelin WG Jr., 2002, How oxygen makes its presence felt. Genes Dev 16: 1441–1445.PubMedCrossRefGoogle Scholar
  10. Kietzmann, T., Samoylenko, A., Roth, U., Jungermann K., 2002, Hypoxia-Inducible Factor-1 And Hypoxia Response Elements Mediate the Induction of Plasminogen Activator Inhibitor-1 Gene Expression by Insulin in Primary Rat Hepatocytes. Blood Sep 12, DOI 10.1182/blood-2002–06-1693 Google Scholar
  11. Kyaw, M., Yoshizumi, M., Tsuchiya, K., Kirima, K., Tamaki, T., 2001, Antioxidants inhibit JNK and p38 MAPK activation but not ERK 1/2 activation by angiotensin II in rat aortic smooth muscle cells. Hypertens Res 24: 251–261.PubMedCrossRefGoogle Scholar
  12. Lambeth, J.D., 2002, Nox/Duox family of nicotinamide adenine dinucleotide (phosphate) oxidases. Curr Opin Hematol 9: 11–17.PubMedCrossRefGoogle Scholar
  13. Li, J., Shworak, N.W., Simons, M., 2002, Increased responsiveness of hypoxic endothelial cells to FGF2 is mediated by HIF-1 alpha-dependent regulation of enzymes involved in synthesis of heparan sulfate FGF2-binding sites. J Cell Sci 115: 1951–1959.PubMedGoogle Scholar
  14. Martindale, J.L., Holbrook, N.J., 2002, Cellular response to oxidative stress: signaling for suicide and survival. J Cell Physiol 192: 1–15.PubMedCrossRefGoogle Scholar
  15. Michiels, C., Minet, E., Mottet, D., Raes, M., 2002, Regulation of gene expression by oxygen: NF-kappaB and HIF-1, two extremes. Free Radic Biol Med 33: 1231–1242.PubMedCrossRefGoogle Scholar
  16. Patterson, C, Stouffer, G.A., Madamanchi, N., Runge, M.S., 2001, New tricks for old dogs: nonthrombotic effects of thrombin in vessel wall biology. Circ Res 88: 987–997.PubMedCrossRefGoogle Scholar
  17. Richard, D.E., Berra, E., Pouyssegur, J., 2000, Nonhypoxic pathway mediates the induction of hypoxia-inducible factor 1alpha in vascular smooth muscle cells. J Biol Chem 275: 26765–26771.PubMedGoogle Scholar
  18. Sandau, K.B., Zhou, J., Kietzmann, T., Brune, B., 2001, Regulation of the hypoxia-inducible factor 1 alpha by the inflammatory mediators nitric oxide and tumor necrosis factor-alpha in contrast to desferroxamine and phenylarsine oxide. J Biol Chem 276: 39805–39811.PubMedCrossRefGoogle Scholar
  19. Semenza, G.L., 2001, Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology. Trends Mol Med 7:345–350.PubMedCrossRefGoogle Scholar
  20. Tacchini, L., Dansi, P., Matteucci, E., Desiderio, M.A., 2001, Hepatocyte growth factor signalling stimulates hypoxia inducible factor-1 (HIF-1) activity in HepG2 hepatoma cells. Carcinogenesis 22: 1363–1371.PubMedCrossRefGoogle Scholar
  21. Zelzer, E., Levy, Y., Kahana, C., Shilo, B.Z., Rubinstein, M., Cohen, B., 1998, Insulin induces transcription of target genes through the hypoxia-inducible factor HIF- lalpha/ARNT. EMBO J 17: 5085–5094.PubMedCrossRefGoogle Scholar
  22. Zhong, H., Chiles, K., Feldser, D., Laughner, E., Hanrahan, C., Georgescu, M.M., Simons, J.W., Semenza, G.L., 2000, Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 60: 1541–1545.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Rachida Siham Bel Aiba
    • 1
  • Agnes Görlach
    • 1
  1. 1.Experimental Pediatric CardiologyGerman Heart Center Munich at the Technical University MunichMunich

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