Clinical and Experimental Pediatrics

대한소아청소년과학회 (The Korean Pediatric Society)
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Hypoxia-inducible factor: role in cell survival in superoxide dismutase overexpressing mice after neonatal hypoxia-ischemia

  • Jeon, Ga Won (Department of Pediatrics, Inje University Busan Paik Hospital, Inje University College of Medicine) ;
  • Sheldon, R. Ann (Departments of Pediatrics and Neurology and Newborn Brain Research Institute, University of California San Francisco) ;
  • Ferriero, Donna M. (Departments of Pediatrics and Neurology and Newborn Brain Research Institute, University of California San Francisco)
  • 투고 : 2019.07.19
  • 심사 : 2019.10.15
  • 발행 : 2019.12.15
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초록

Background: Sixty percent of infants with severe neonatal hypoxic-ischemic encephalopathy die, while most survivors have permanent disabilities. Treatment for neonatal hypoxic-ischemic encephalopathy is limited to therapeutic hypothermia, but it does not offer complete protection. Here, we investigated whether hypoxia-inducible factor (HIF) promotes cell survival and suggested neuroprotective strategies. Purpose: HIF-1α deficient mice have increased brain injury after neonatal hypoxia-ischemia (HI), and the role of HIF-2α in HI is not well characterized. Copper-zinc superoxide dismutase (SOD)1 overexpression is not beneficial in neonatal HI. The expression of HIF-1α and HIF-2α was measured in SOD1 overexpressing mice and compared to wild-type littermates to see if alteration in expression explains this lack of benefit. Methods: On postnatal day 9, C57Bl/6 mice were subjected to HI, and protein expression was measured by western blotting in the ipsilateral cortex of wild-type and SOD1 overexpressing mice to quantify HIF-1α and HIF-2α. Spectrin expression was also measured to characterize the mechanism of cell death. Results: HIF-1α protein expression did not significantly change after HI injury in the SOD1 overexpressing or wild-type mouse cortex. However, HIF-2α protein expression increased 30 minutes after HI injury in the wild-type and SOD1 overexpressing mouse cortex and decreased to baseline value at 24 hours after HI injury. Spectrin 145/150 expression did not significantly change after HI injury in the SOD1 overexpressing or wild-type mouse cortex. However, spectrin 120 expression increased in both wild-type and SOD1 overexpressing mouse at 4 hours after HI, which decreased by 24 hours, indicating a greater role of apoptotic cell death. Conclusion: HIF-1α and HIF-2α may promote cell survival in neonatal HI in a cell-specific and regional fashion. Our findings suggest that early HIF-2α upregulation precedes apoptotic cell death and limits necrotic cell death. However, the influence of SOD was not clarified; it remains an intriguing factor in neonatal HI.

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참고문헌

  1. Volpe JJ. Hypoxic-ischemic injury in the term infant: pathophysiology. In: Volpe JJ, Inder TE, Darras BT, de Vries LS, du Plessis AJ, Neil JJ, et al., editors. Volpe's neurology of the newborn. 6th ed. Philadelphia (PA): Elsevier, 2018:500-9.
  2. Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005;353:1574-84. https://doi.org/10.1056/NEJMcps050929
  3. Gonzalez FF, Ferriero DM. Neuroprotection in the newborn infant. Clin Perinatol 2009;36:859-80, vii. https://doi.org/10.1016/j.clp.2009.07.013
  4. Sheldon RA, Osredkar D, Lee CL, Jiang X, Mu D, Ferriero DM. HIF-1 alpha-deficient mice have increased brain injury after neonatal hypoxia-ischemia. Dev Neurosci 2009;31:452-8. https://doi.org/10.1159/000232563
  5. Bernaudin M, Tang Y, Reilly M, Petit E, Sharp FR. Brain genomic response following hypoxia and re-oxygenation in the neonatal rat. Identification of genes that might contribute to hypoxia-induced ischemic tolerance. J Biol Chem 2002;277:39728-38. https://doi.org/10.1074/jbc.M204619200
  6. Ran R, Xu H, Lu A, Bernaudin M, Sharp FR. Hypoxia preconditioning in the brain. Dev Neurosci 2005;27:87-92. https://doi.org/10.1159/000085979
  7. Bergeron M, Gidday JM, Yu AY, Semenza GL, Ferriero DM, Sharp FR. Role of hypoxia-inducible factor-1 in hypoxia-induced ischemic tolerance in neonatal rat brain. Ann Neurol 2000;48:285-96. https://doi.org/10.1002/1531-8249(200009)48:3<285::AID-ANA2>3.0.CO;2-8
  8. Ditelberg JS, Sheldon RA, Epstein CJ, Ferriero DM. Brain injury after perinatal hypoxia-ischemia is exacerbated in copper/zinc superoxide dismutase transgenic mice. Pediatr Res 1996;39:204-8.
  9. Yang G, Chan PH, Chen J, Carlson E, Chen SF, Weinstein P, et al. Human copper-zinc superoxide dismutase transgenic mice are highly resistant to reperfusion injury after focal cerebral ischemia. Stroke 1994;25:165-70. https://doi.org/10.1161/01.STR.25.1.165
  10. Lafemina MJ, Sheldon RA, Ferriero DM. Acute hypoxia-ischemia results in hydrogen peroxide accumulation in neonatal but not adult mouse brain. Pediatr Res 2006;59:680-3. https://doi.org/10.1203/01.pdr.0000214891.35363.6a
  11. Sheldon RA, Jiang X, Francisco C, Christen S, Vexler ZS, Tauber MG, et al. Manipulation of antioxidant pathways in neonatal murine brain. Pediatr Res 2004;56:656-62. https://doi.org/10.1203/01.PDR.0000139413.27864.50
  12. Rice JE 3rd, Vannucci RC, Brierley JB. The influence of immaturity on hypoxic-ischemic brain damage in the rat. Ann Neurol 1981;9:131-41. https://doi.org/10.1002/ana.410090206
  13. Vannucci RC, Vannucci SJ. Perinatal hypoxic-ischemic brain damage: evolution of an animal model. Dev Neurosci 2005;27:81-6. https://doi.org/10.1159/000085978
  14. Wang X, Zhu C, Wang X, Hagberg H, Korhonen L, Sandberg M, et al. X-linked inhibitor of apoptosis (XIAP) protein protects against caspase activation and tissue loss after neonatal hypoxia-ischemia. Neurobiol Dis 2004;16:179-89. https://doi.org/10.1016/j.nbd.2004.01.014
  15. Chang S, Jiang X, Zhao C, Lee C, Ferriero DM. Exogenous low dose hydrogen peroxide increases hypoxia-inducible factor-1alpha protein expression and induces preconditioning protection against ischemia in primary cortical neurons. Neurosci Lett 2008;441:134-8. https://doi.org/10.1016/j.neulet.2008.06.005
  16. Ferriero DM. Neonatal brain injury. N Engl J Med 2004;351:1985-95. https://doi.org/10.1056/NEJMra041996
  17. Buonocore G, Groenendaal F. Anti-oxidant strategies. Semin Fetal Neonatal Med 2007;12:287-95. https://doi.org/10.1016/j.siny.2007.01.020
  18. Li L, Yin X, Ma N, Lin F, Kong X, Chi J, et al. Desferrioxamine regulates HIF-1 alpha expression in neonatal rat brain after hypoxiaischemia. Am J Transl Res 2014;6:377-83.
  19. Hamrick SE, McQuillen PS, Jiang X, Mu D, Madan A, Ferriero DM. A role for hypoxia-inducible factor-1alpha in desferoxamine neuroprotection. Neurosci Lett 2005;379:96-100. https://doi.org/10.1016/j.neulet.2004.12.080
  20. Zhang L, Qu Y, Yang C, Tang J, Zhang X, Mao M, et al. Signaling pathway involved in hypoxia-inducible factor-1alpha regulation in hypoxic-ischemic cortical neurons in vitro. Neurosci Lett 2009;461:1-6. https://doi.org/10.1016/j.neulet.2009.03.091
  21. Chavez JC, Baranova O, Lin J, Pichiule P. The transcriptional activator hypoxia inducible factor 2 (HIF-2/EPAS-1) regulates the oxygendependent expression of erythropoietin in cortical astrocytes. J Neurosci 2006;26:9471-81. https://doi.org/10.1523/JNEUROSCI.2838-06.2006
  22. Yeo EJ, Cho YS, Kim MS, Park JW. Contribution of HIF-1alpha or HIF-2alpha to erythropoietin expression: in vivo evidence based on chromatin immunoprecipitation. Ann Hematol 2008;87:11-7. https://doi.org/10.1007/s00277-007-0359-6
  23. Trollmann R, Gassmann M. The role of hypoxia-inducible transcription factors in the hypoxic neonatal brain. Brain Dev 2009;31:503-9. https://doi.org/10.1016/j.braindev.2009.03.007
  24. Sheldon RA, Lee CL, Jiang X, Knox RN, Ferriero DM. Hypoxic preconditioning protection is eliminated in HIF-$1{\alpha}$ knockout mice subjected to neonatal hypoxia-ischemia. Pediatr Res 2014;76:46-53. https://doi.org/10.1038/pr.2014.53
  25. Sheldon RA, Sadjadi R, Lam M, Fitzgerald R, Ferriero DM. Alteration in downstream hypoxia gene signaling in neonatal glutathione peroxidase overexpressing mouse brain after hypoxia-ischemia. Dev Neurosci 2015;37:398-406. https://doi.org/10.1159/000375369
  26. Nanduri J, Wang N, Yuan G, Khan SA, Souvannakitti D, Peng YJ, et al. Intermittent hypoxia degrades HIF-2alpha via calpains resulting in oxidative stress: implications for recurrent apnea-induced morbidities. Proc Natl Acad Sci U S A 2009;106:1199-204. https://doi.org/10.1073/pnas.0811018106
  27. Zhu C, Yu J, Pan Q, Yang J, Hao G, Wang Y, et al. Hypoxia-inducible factor-2 alpha promotes the proliferation of human placenta-derived mesenchymal stem cells through the MAPK/ERK signaling pathway. Sci Rep 2016;6:35489. https://doi.org/10.1038/srep35489
  28. Koeppen M, Lee JW, Seo SW, Brodsky KS, Kreth S, Yang IV, et al. Hypoxia-inducible factor 2-alpha-dependent induction of amphiregulin dampens myocardial ischemia-reperfusion injury. Nat Commun 2018;9:816. https://doi.org/10.1038/s41467-018-03105-2
  29. Semenza GL, Prabhakar NR. The role of hypoxia-inducible factors in carotid body (patho) physiology. J Physiol 2018;596:2977-83. https://doi.org/10.1113/JP275696
  30. Chavez-Valdez R, Martin LJ, Flock DL, Northington FJ. Necrostatin-1 attenuates mitochondrial dysfunction in neurons and astrocytes following neonatal hypoxia-ischemia. Neuroscience 2012;219:192-203. https://doi.org/10.1016/j.neuroscience.2012.05.002
  31. Epstein CJ, Avraham KB, Lovett M, Smith S, Elroy-Stein O, Rotman G, et al. Transgenic mice with increased Cu/Zn-superoxide dismutase activity: animal model of dosage effects in Down syndrome. Proc Natl Acad Sci U S A 1987;84:8044-8. https://doi.org/10.1073/pnas.84.22.8044

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