Hypoxia-Inducible Factor-1α Accumulation in the Rat Brain in Response to Hypoxia and Ischemia is Attenuated During Aging

  • Juan C. Chavez
  • Joseph C. LaManna
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 510)

Abstract

A common feature of senescent organisms is the decline in their ability to respond to different types of stress such as hypoxia or ischemia. Previously it was reported that aging was associated with a defect in compensatory angiogenesis in response to tissue ischemia. This deficit was associated to a reduction of vascular endothelial growth factor (VEGF) expression, an endothelial-specific mitogen that is essential for angiogenesis during development and adulthood. VEGF as well as other hypoxia-responsive genes share a common regulatory pathway. They are regulated by the transcription factor hypoxia inducible factor-1 (HIF-1), a heterodimeric protein consisting of two subunits, HIF-1a and HIF-113. Both subunits are required for DNA binding and transactivation of target genes. HIF-la is unique to HIF-1 and its expression is primarily regulated by oxygen tension. During normoxia the HIF-la gene is expressed continuously; however, the HIE-la protein is rapidly degraded by the ubiquitin-proteosome system. During hypoxia, degradation of HIF-la is suppressed and thereby it accumulates in the nucleus almost instantly. In contrast, the HIP-113 subunit is constitutively expressed and its levels do not change significantly during hypoxia

Keywords

Catheter Glycerol Ischemia Albumin EDTA 

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References

  1. 1.
    Rivard, J-E. Fabre, M. Silver, D. Chen, T. Murohara, M. Kearney, M. Magner, T. Asahara, J. Isner, Age-dependent impairment of angiogenesis, Circulation 99, 111–120 (1999).PubMedCrossRefGoogle Scholar
  2. 2.
    G. Neufeld, T. Cohen, S. Gengrinovitch, Z. Poltoral, Vascular endothelial growth factor (VEGF) and its receptors. FASEB J. 12, 9–22 (1999).Google Scholar
  3. 3.
    G.L. Wang, B-H Jiang, E.A. Rue, G.L. Semenza, Hypoxia inducible factor-1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular 02 tension, Proc. Natl. Acad. Sci. USA 92, 5510–5514 (1995).PubMedCrossRefGoogle Scholar
  4. 4.
    LE. Huang, J. Gu, M. Schau, F.H. Bunn, Regulation of hypoxia-inducible factor la is mediated by an Or dependent degradation domain via the ubiquitin-proteosome pathway, Proc. Natl. Acad. Sci. USA 95, 7987–7992 (1998).PubMedCrossRefGoogle Scholar
  5. 5.
    S. Salceda, J. Caro, Hypoxia-inducible factor la (HIF-1a) protein is rapidly degraded by the ubiquitinproteosome system under normoxic conditions, J. Biol Chem 272, 22642–22647 (1997).PubMedCrossRefGoogle Scholar
  6. 6.
    U.R. Jewell, I Kvietikova, A. Scheid, R. H. Wenger, M. Gassmann. Induction of HIF-la in response to hypoxia is instantaneous. FASEB J. 15, 1312–1314 (2001).PubMedGoogle Scholar
  7. 7.
    C. Crumrine, J.C. LaManna Regional cerebral metabolites, blood flow, plasma volume, and mean transit time in total cerebral ischemia in the rat, J Cereb Blood Flow Metab. 11, 272–282 (1991).PubMedCrossRefGoogle Scholar
  8. 8.
    K.L. Jin, X.O. Mao, D.A. Greenberg. Vascular endothelial growth factor: direct neuroprotective effect in in-vitro ischemia, Proc.Natl. Acad. Sci. USA 97, 10242–10247 (2000).PubMedCrossRefGoogle Scholar
  9. 9.
    M. Sondell, G. Lundborg, M. Kanje. Vascular endothelial growth factor has neurotrophic activities and stimulates axonal autogrowth, enhancing cell survival and Schwann cell proliferation in the peripheral nervous system. J Neurosci 19, 5731–5740 (1999)PubMedGoogle Scholar
  10. 10.
    N.S. Chandel, D.S. McClintock, C.E. Feliciano, T.M. Wood, J.A. Melendez, A. M. Rodrigues, PT. Schumacker. Reactive oxygen species generated at mitochondria) complex Ill stabilize hypoxia-inducible factor la during hypoxia. J Biol Chem 275 25130–25138 (2000)PubMedCrossRefGoogle Scholar
  11. 11.
    F. H. Agani, P. Pichiule, J.C. Chavez, JC. LaManna. The role of mitochondria in the regulation of hypoxiainducible factor 1 expression during hypoxia. J Biol Chem 275, 35863–35867 (2000).PubMedCrossRefGoogle Scholar
  12. 12.
    E. C. Vaux, E. Metzen, K. M. Yeates, P. J. Ratcliffe. Regulation of hypoxia inducible factor is preserved in the absence of a functioning mitochondria) respiratory chain. Blood 98, 296–302 (2001).PubMedCrossRefGoogle Scholar
  13. 13.
    V. Srinivas, I. Leshchinsky, N. Sang, M.P. King, A. Minchenko, J. Caro. Oxygen sensing and HIF-1 activation does not require an active mitochondria) respiratory chain electron-transfer pathway. J Biol Chem. 276, 21995–21998 (2001).PubMedCrossRefGoogle Scholar
  14. 14.
    G. Frenkel-Denkberg, D. Gershon, A. P. Levy. The function of hypoxia-inducible factor 1 (HIF-1) is impaired in senescent mice. FEBS Letters 462: 341–344 (1999)PubMedCrossRefGoogle Scholar
  15. 15.
    A. Rivardi, L Berthou-Soulie, N. Principe, M. Kearney, C. Curry, D. Branellec, G. L. Semenza, J. M. Isner. Age-dependent defect in vascular endothelial growth factor expression is associated with reduced hypoxia-inducible factor 1 activity, J. Biol Chem 275, 29643–29647 (2000).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Juan C. Chavez
    • 1
  • Joseph C. LaManna
    • 1
  1. 1.Case Western Reserve UniversityDepartment of AnatomyCleveland

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