Skip to main content

Advertisement

SpringerLink
Log in

HIF-1α subunit and vasoactive HIF-1-dependent genes are involved in carbon monoxide-induced cerebral hypoxic stress response

  • Original Article
  • Published:
European Journal of Applied Physiology Aims and scope Submit manuscript

Abstract

Hypoxia-inducible transcription factor-1 (HIF-1) is the most important component of cellular and molecular adaptive responses to hypoxia. We aimed to analyze effects of systemic hypoxia and CO exposure on the oxygen-regulated α-subunit of HIF-1 and HIF-1-dependent vasoactive target genes in rat brain. Brains of adult Sprague–Dawley rats were investigated after incubation for 3 and 12 h under normoxia, hypoxia (8% O2) and CO 0.1% (n = 10 per group). Upon 3 h of exposure, hypoxia and CO-induced accumulation of HIF-1α protein in brain homogenates assessed by Western blot analysis. In contrast to hypoxia HIF-1α signals decreased markedly during 12 h-exposure to CO. By immunohistochemistry, intensive HIF-1α-positive staining was found in neurons of the cortex and hippocampus. Cerebral expression of vasoactive target genes adrenomedullin (ADM) and vascular endothelial growth factor (VEGF) showed up-regulation during both hypoxia and CO exposure indicating functional activation of HIF-1. Hypoxia increased ADM (P < 0.05) and VEGF mRNA levels within 3 h (P < 0.01) which persisted up to 12 h of exposure (ADM, P < 0.05; VEGF, P < 0.001). Similarly, CO inhalation led to early up-regulation of VEGF (3 h: P < 0.05; 12 h: P < 0.01), but a more delayed increase of ADM mRNA levels (3 h: n.s., 12 h: P < 0.01). We suggest that CO-induced oxygen deprivation is a potent stimulus to cerebral HIF-1-regulated hypoxic stress responses even though its effects are more transient than exposure to hypoxia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Abe M, Sata M, Nishimatsu H, Nagata D, Suzuki E, Terauchi Y, Kadowaki T, Minamino N, Kangawa K, Matsuo H, Hirata Y, Nagai R (2003) Adrenomedullin augments collateral development in response to acute ischemia. Biochem Biophys Res Commun 306:10–15. doi:10.1016/S0006-291X(03)00903-3

    Article  PubMed  CAS  Google Scholar 

  • Bergeron M, Yu AY, Solway KE, Semenza GL, Sharp FR (1999) Induction of hypoxia-inducible factor-1 and its target genes following focal ischemia in rat brain. Eur J Neurosci 11:4159–4170. doi:10.1046/j.1460-9568.1999.00845.x

    Article  PubMed  CAS  Google Scholar 

  • Berchner-Pfannschmidt U, Yamac H, Trinidad B, Fandrey J (2007) Nitric oxide modulates oxygen sensing by hypoxia-inducible factor 1-dependent induction of prolyl hydroxylase 2. J Biol Chem 282:1788–1796

    Article  PubMed  CAS  Google Scholar 

  • Bernaudin M, Nedelec AS, Divoux D, MacKenzie ET, Petit E, Schumann-Bard P (2002) Normobaric hypoxia induces tolerance to focal permanent cerebral ischemia in association with an increased expression of hypoxia-inducible factor-1 and its target genes, erythropoietin and VEGF, in the adult mouse brain. J Cereb Blood Flow Metab 22:393–403. doi:10.1097/00004647-200204000-00003

    Article  PubMed  CAS  Google Scholar 

  • Brain SD, Grant AD (2004) Vascular actions of calcitonin gene-related peptide and adrenomedullin. Physiol Rev 84:903–934. doi:10.1152/physrev.00037.2003

    Article  PubMed  CAS  Google Scholar 

  • Chavez JC, LaManna JC (2002) Activation of hypoxia-inducible factor-1 in the rat cerebral cortex after transient global ischemia: potential role of insulin-like growth factor 1. J Neurosci 22:8922–8931

    PubMed  CAS  Google Scholar 

  • Chavez JC, Agani F, Pichiule P, LaManna JC (2000) Expression of hypoxia—inducible factor-1α in the brain of rats during chronic hypoxia. J Appl Physiol 89:1937–1942

    PubMed  CAS  Google Scholar 

  • Chin BY, Jiang G, Wegiel B, Wang HJ, MacDonald T, Zhang XC, Gallo D, Cszimadia D, Bach FH, Lee PJ, Otterbein LE (2007) Hypoxia-inducible factor 1α stabilization by carbon monoxide results in cytoprotective preconditioning. Proc Natl Acad Sci USA 104:5109–5114. doi:10.1073/pnas.0609611104

    Article  PubMed  CAS  Google Scholar 

  • Choi S (2000) Delayed neurological sequelae in carbon monoxide intoxication. Arch Neurol 57:1214–1218. doi:10.1001/archneur.57.8.1214

    Article  Google Scholar 

  • D’Angelo G, Duplan E, Boyer N, Vigne P, Frelin C (2003) Hypoxia up-regulates prolyl hydroxylase activity: a feedback mechanism that limits HIF-1 responses during reoxygenation. J Biol Chem 278:38183–38187. doi:10.1074/jbc.M302244200

    Article  PubMed  CAS  Google Scholar 

  • Ernst A, Zibrak JD (1998) Carbon monoxide poisoning. N Engl J Med 339:1603–1608. doi:10.1056/NEJM199811263392206

    Article  PubMed  CAS  Google Scholar 

  • Fandrey J, Gorr TA, Gassmann M (2006) Regulating cellular oxygen sensing by hydroxylation. Cardiovasc Res 71:642–651. doi:10.1016/j.cardiores.2006.05.005

    Article  PubMed  CAS  Google Scholar 

  • Gerber HP, Condorelli F, Park J, Ferrara N (1997) Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia. J Biol Chem 272:23659–23667. doi:10.1074/jbc.272.38.23659

    Article  PubMed  CAS  Google Scholar 

  • Hofbauer KH, Jensen BL, Kurtz A, Sandner P (2000) Tissue hypoxygenation activates the adrenomedullin system in vivo. Am J Physiol 278:R513–R519

    CAS  Google Scholar 

  • Höpfl G, Ogunshola O, Gassmann M (2003) Hypoxia and high altitude. The molecular response. Adv Exp Med Biol 543:89–115

    PubMed  Google Scholar 

  • Huang LE, Willmore WG, Gu J, Goldberg MA, Bunn HF (1999) Inhibition of hypoxia-inducible factor 1 activation by carbon monoxide and nitric oxide. Implications for oxygen sensing and signaling. J Biol Chem 274:9038–9044. doi:10.1074/jbc.274.13.9038

    Article  PubMed  CAS  Google Scholar 

  • Jansen-Olesen K, Jorgensen L, Engel U, Edvinsson L (2003) In-depth characterization of CGRP receptors in human intracranial arteries. Eur J Pharmacol 481:207–216. doi:10.1016/j.ejphar.2003.09.021

    Article  PubMed  CAS  Google Scholar 

  • Jiang BH, Semenza GL, Bauer C, Marti HH (1996) Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am J Physiol 271:C1172–C1180

    PubMed  CAS  Google Scholar 

  • Jin KL, Mao XO, Nagayama T, Goldsmith PC, Greenberg DA (2000) Induction of vascular endothelial growth factor and hypoxia-inducible factor-1α by global ischemia in rat brain. Neuroscience 99:577–585. doi:10.1016/S0306-4522(00)00207-4

    Article  PubMed  CAS  Google Scholar 

  • Jin K, Zhu Y, Sun Y, Mao XO, Xie L, Greenberg DA (2002) Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci USA 99:11946–11950. doi:10.1073/pnas.182296499

    Article  PubMed  CAS  Google Scholar 

  • Kis B, Abraham CS, Deli MA, Kobayashi H, Wada A, Niwa M, Yamashita H, Ueta Y (2001) Adrenomedullin in the cerebral circulation. Peptides 22:1825–1834. doi:10.1016/S0196-9781(01)00533-2

    Article  PubMed  CAS  Google Scholar 

  • Ladoux A, Frelin C (2000) Coordinated up-regulation by hypoxia of adrenomedullin and one of its putative receptors (RDC-1) in cells of the rat blood-brain barrier. J Biol Chem 275:39914–39919. doi:10.1074/jbc.M006512200

    Article  PubMed  CAS  Google Scholar 

  • Lo CP, Chen SY, Lee KW, Chen WL, Chen CY, Hsueh CJ, Huang GS (2007) Brain injury after acute carbon monoxide poisoning: early and late complications. Am J Roentgenol 189:W205–W211. doi:10.2214/AJR.07.2425

    Article  Google Scholar 

  • Marti HJ, Bernaudin M, Bellail A, Schoch H, Euler M, Petit E, Risau W (2000) Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia. Am J Pathol 156:965–976

    PubMed  CAS  Google Scholar 

  • Prockop LD, Chichkova RI (2007) Carbon monoxide intoxication: an updated review. J Neurol Sci 262:122–130. doi:10.1016/j.jns.2007.06.037

    Article  PubMed  CAS  Google Scholar 

  • Rosenberger C, Mandriota S, Jurgensen JS, Wiesener MS, Horstrup JH, Frei U, Ratcliffe PJ, Maxwell PH, Bachmann S, Eckardt KU (2000) Expression of hypoxia-inducible factor-1α and -2α in hypoxic and ischemic rat kidneys. J Am Soc Nephrol 13:1721–1732. doi:10.1097/01.ASN.0000017223.49823.2A

    Article  CAS  Google Scholar 

  • Sandau KB, Zhou J, Kietzmann T, Brune B (2001) Regulation of the hypoxia-inducible factor 1α by the inflammatory mediators nitric oxide and tumor necrosis factor-α in contrast to desferroxamine and phenylarsine oxide. J Biol Chem 276:39805–39811. doi:10.1074/jbc.M107689200

    Article  PubMed  CAS  Google Scholar 

  • Shao G, Gao CY, Lu GW (2005) Alterations of hypoxia-inducible factor-1 alpha in the hippocampus of mice acutely and repeatedly exposed to hypoxia. Neurosignals 14:255–261. doi:10.1159/000088641

    Article  PubMed  CAS  Google Scholar 

  • Shih SC, Claffey KP (2001) Role of AP-1 and HIF-1 transcription factors in TGF-beta activation of VEGF expression. Growth Factors 19:19–34

    Article  PubMed  CAS  Google Scholar 

  • Stiehl DP, Wirthner R, Köditz J, Spielmann P, Camenisch G, Wenger RH (2006) Increased prolyl 4-hydroxylase domain proteins compensate for decreased oxygen levels. Evidence for an autoregulatory oxygen-sensing system. J Biol Chem 281:23482–23491. doi:10.1074/jbc.M601719200

    Article  PubMed  CAS  Google Scholar 

  • Stroka DM, Burkhardt T, Desbaillets I, Wenger RH, Neil DAH, Bauer C, Gassmann M, Candinas D (2001) HIF-1 is expressed in normoxic tissues and displays an organ-specific regulation under systemic hypoxia. FASEB J 15:2445–2453

    PubMed  CAS  Google Scholar 

  • Sugo S, Minamino N, Shoji H, Kangawa K, Kitamura K, Eto T, Matsuo H (1995) Interleukin-1, tumor necrosis factor and lipopolysaccharide additively stimulate production of adrenomedullin in vascular smooth muscle cells. Biochem Biophys Res Commun 207:25–32. doi:10.1006/bbrc.1995.1148

    Article  PubMed  CAS  Google Scholar 

  • Sun Y, Jin K, Xie L, Childs J, Mao XO, Logvinova A, Greenberg DA (2003) VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest 111:1843–1851

    PubMed  CAS  Google Scholar 

  • Tang Y, Pacary E, Freret T, Divoux D, Petit E, Schumann-Bard P, Bernaudin M (2006) Effect of hypoxic preconditioning on brain genomic response before and following ischemia in the adult mouse: identification of potential neuroprotective candidates for stroke. Neurobiol Dis 21:18–28. doi:10.1016/j.nbd.2005.06.002

    Article  PubMed  CAS  Google Scholar 

  • Tofighi R, Tillmark N, Daré E, Aberg AM, Larsson JE, Ceccatelli S (2006) Hypoxia-independent apoptosis in neural cells exposed to carbon monoxide in vitro. Brain Res 1098:1–8. doi:10.1016/j.brainres.2006.04.095

    Article  PubMed  CAS  Google Scholar 

  • Trollmann R, Schoof E, Beinder E, Wenzel D, Rascher W, Dötsch J (2002) Adrenomedullin gene expression in human placental tissue and leukocytes: a potential marker of severe tissue hypoxia in neonates with birth asphyxia. Eur J Endocrinol 147:711–716. doi:10.1530/eje.0.1470711

    Article  PubMed  CAS  Google Scholar 

  • Watanabe K, Takayasu M, Noda A, Hara M, Takagi T, Suzuki Y, Yoshia J (2001) Adrenomedullin reduces ischemic brain injury after transient middle cerebral artery occlusion in rats. Acta Neurochir 143:1157–1161. doi:10.1007/s007010100007

    Article  CAS  Google Scholar 

  • Xia CF, Yin H, Borlongan CV, Chao J, Chao L (2004) Adrenomedullin gene delivery protects against cerebral ischemic injury by promoting astrocyte migration and survival. Hum Gene Ther 15:1243–1254. doi:10.1089/hum.2004.15.1243

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors are thankful to Dr. Karl-Heinz Hofbauer (University of Regensburg, Germany) for his support of the animal experiments. The study was supported by ELAN Fonds of the Medical Faculty of the University of Erlangen-Nuremberg (to R.T).

Author information

Authors and Affiliations

  1. Department of Pediatrics, Friedrich-Alexander-University of Erlangen-Nuremberg, Loschgestrasse 15, 91054, Erlangen, Germany

    S. Bani Hashemi, J. Braun, W. Rascher, J. Dötsch & R. Trollmann

  2. Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Krankenhausstr. 12, Erlangen, Germany

    W. M. Bernhardt

Authors
  1. S. Bani Hashemi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Braun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. W. M. Bernhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. W. Rascher
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. Dötsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R. Trollmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R. Trollmann.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bani Hashemi, S., Braun, J., Bernhardt, W.M. et al. HIF-1α subunit and vasoactive HIF-1-dependent genes are involved in carbon monoxide-induced cerebral hypoxic stress response. Eur J Appl Physiol 104, 95–102 (2008). https://doi.org/10.1007/s00421-008-0776-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00421-008-0776-9

Keywords

Search

Navigation