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Cellular Adaptive Responses to Low Oxygen Tension: Apoptosis and Resistance

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Abstract

Oxygen plays such a critical role in the central nervous system that a specialized mechanism of oxygen delivery to neurons is required. Reduced oxygen tension, or hypoxia, may have severe detrimental effects on neuronal cells. Several studies suggest that hypoxia can induce cellular adaptive responses that overcome apoptotic signals in order to minimize hypoxic injury or damage. Adaptive responses of neuronal cells to hypoxia may involve activation of various ion channels, as well as induction of specific gene expression. For example, ATP sensitive K+ channels are activated by hypoxia in selective neuronal cells, and may play a role in cell survival during hypoxia/anoxia. Additionally, hypoxia-induced c-Jun, bFGF and NGF expression appear to be associated with prevention (or delay) of neuronal cell apoptosis. In this paper, these adaptive responses to hypoxia in neuronal cells are discussed to examine the possible role of hypoxia in pathophysiology of diseases.

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REFERENCES

  1. Graham, D. I., Adams, J. H., and Gennarelli, T. A. 1993. Pathology of brain damage in head injury. Pages 91–113, in Cooper P. R. (ed), Head Injury, Williams & Wilkins, Baltimore.

    Google Scholar 

  2. Fruchart, J. C., and Dariez, P. 1994. Free radicals and atherosclerosis. Pages 257–280, in Rice-Evans, C. A., and Burdon, R. H. (eds.), Free radical damage and its control, Elsevier, Amsterdam.

    Google Scholar 

  3. Daut, J., Maier-Rudolph, W., von Beckerath, N., Mehrke, G., Gunter, K., and Goedel-Meinin, L. 1990. Hypoxic dilation of coronary arteries is mediated by ATP-sensitive potassium channels. Science 247:1341–1344.

    Google Scholar 

  4. Ganfornia, M. D., and Lopez-Barneo, J. 1991. Single K+ channels in membrane patches of arterial chemoreceptor cells are modulated by O2 tension. Proc. Natl. Acad. Sci. USA. 88:2927–2930.

    Google Scholar 

  5. Cornfield, D. N., Stevens, T., McMurtry, I. F., Abman, S. H., and Rodman, D. M. 1994. Acute hypoxia causes membrane depolarization and calcium influx in fetal pulmonary artery smooth muscle cells. Am. J. Physiol. 266:L469-L475.

    Google Scholar 

  6. Haddad, G. G., and Jiang, C. 1994. Mechanisms of neuronal survival during hypoxia: ATP-sensitive K+ channels. Biol. Neonate 65:160–165.

    Google Scholar 

  7. Muschel, R. J., Bernhard, E. J., Garza, L., McKenna, W. G., and Koch, C. J. 1995. Induction of apoptosis at different oxygen tension: Evidence that oxygen radicals do not mediate apoptotic signaling. Cancer Res. 55:995–998.

    Google Scholar 

  8. Shimizu, S., Eguchi, Y., Kamiike, W., Itoh, Y., Hasegawa, J-I., Yomabe, K., Otsuki, Y., Matsuda, H., and Tsujimoto, Y. 1996. Induction of apoptosis as well as necrosis by hypoxia and predominant prevention of apoptosis by Bcl-2 and Bcl-XL. Cancer Res. 56:2161–2166.

    Google Scholar 

  9. Hannah, S., Mecklenburgh, K., Rahman, I., Bellingan, G. J., Greening, A., Haslett, C., and Chilvers, E. R. 1995. Hypoxia prolongs neutrophil survival in vitro. FEBS Lett. 372:233–237.

    Google Scholar 

  10. Haddad, G. G., and Jiang, C. 1993. O2 deprivation in the central nervous system: on mechanisms of neuronal responsive, differential sensitivity and injury. Prog. Neurobiol. 40:277–318.

    Google Scholar 

  11. Siesjo, B. K. 1988. Historical overview: Calcium, ischemia, and death of brain cells. Ann. N.Y. Acad. Sci. 522:638–661.

    Google Scholar 

  12. Szatkowski, M., and Attwell, D. 1994. Triggering and execution of neuronal death in brain ischaemia: two phases of glutamate released by different mechanisms. Trends in Neurosci. 17:359–365.

    Google Scholar 

  13. Estus, Y., Zaks, W. J., Freeman, R. S., Gruda, M., Bravo, R., and Johnson, E. M. Jr. 1994. Altered gene expression in neurons during programmed cell death:identification of c-Jun as necessary for neuronal apoptosis. J. Cell Biol. 127:1717–1727.

    Google Scholar 

  14. Gagliardini, V., Fernandez, P. A., Lee, R. K., Drexler, H. C., Rotello, R. J., Fishman, M. C., and Yuan, J. 1994. Prevention of vertebrate neuronal death by the Crm A gene. Science 263:826–828.

    Google Scholar 

  15. Greenlund, L. J., Deckwerth, T. L., and Johnson, E. M. Jr. 1995. Superoxide dismutase delays neuronal apoptosis: a role for reactive oxygen species in programmed neuronal death. Neurons 14:303–315.

    Google Scholar 

  16. Akaneya, Y., Enokido, Y., Takahashi, M., and Hatanaka, H. 1993. In vitro model of hypoxia:basic fibroblast growth factor can rescue cultured CNS neurons from oxygen-deprived cell death. J. Cerebral. Blood flow & Metabol. 13:1029–1032.

    Google Scholar 

  17. Holtzman, D. M., Sheldon, R. A., Jaffe, W., Cheng, Y., and Ferriero, D. M. 1996. Nerve growth factor protects the neonatal brain against hypoxic-ischemic injury. Annals of Neurol. 39:114–122.

    Google Scholar 

  18. LaMana, J. C., Boehm, K. D., Mironov, V., Hudetz, A. Z., Hritz, M. A., Yun, J. K., and Harik, S. I. 1994. Increased basic fibroblast growth factor mRNA in the brains of rats exposed to hypobaric hypoxia. Pages 497–502, in Hogan, M. C., Mathieu-Costello, O, Poole, D. C., and Wagner, P. D. (eds.), Oxygen transport to tissue XIV (Adv. Exp. Med. & Biol. v. 36), Plenum Pub, Corp., New York.

    Google Scholar 

  19. Lorez, H., Keller, F., Ruess, G., and Otten, U. 1989. Nerve growth factor increases in adult rat brain after hypoxic injury. Neuroscience Lett. 98:330–344.

    Google Scholar 

  20. Rosenbaum, D. M., Michaelson, M., Batler, D. K., Doshi, P., and Kessler, J. A. 1994. Evidence for hypoxia-induced, programmed cell death of cultured neurons. Ann. Neurol. 36:864–870.

    Google Scholar 

  21. Ashcroft, F. M. 1988. Adenosine 5′-triphosphate-sensitive potassium channels. Annu. Rev. Neurosci. 11:97–118.

    Google Scholar 

  22. Jiang, C., and Haddad, G. G. 1991. Effect of anoxia on intracellular and extracellular potassium activity in hypoglosal neurons in vitro. J. Neurophysiol. 66:103–111.

    Google Scholar 

  23. Dragunow, M., Beilharz, E., Sirimunne, E., Lawlor, P., Williams, C., Bravo, R., and Gluckman, P. 1994. Immediate-early gene protein expression in neurons undergoing delayed death, but not necrosis, following hypoxic-ischaemic injury to the young rat brain. Brain Research. Mol. Brain Res. 25:19–33.

    Google Scholar 

  24. Ianvareva, I. N., and Kuzmina, T. R. 1991. Adaptation to short term acute hypoxia as a factor in enhancing resistance. Fiziologi Cheskii Zhurnal SSSR Imeni I.M. Sechenova. 77:107–111.

    Google Scholar 

  25. Falanga, V., Qian, S. W., Danielpour, D., Katz, M. H., Roberts, A. B., and Sporn, M. B. 1991 Hypoxia upregulates the synthesis of TGF-beta 1 by human dermal fibroblasts. J. Invest. Dermatol. 97:634–637.

    Google Scholar 

  26. Goldberg, M. A., and Schneider, T. J. 1994. Similarities between the oxygen-sensing mechanisms regulating the expression of vascular endothelial growth factor and erythropoietin. J. Biol. Chem. 269:4355–4359.

    Google Scholar 

  27. Sciandra, J. J., Subjeck, J. R., and Hughes, C. S. 1984 Induction of glucose-regulated proteins during anaerobic exposure and heat-shock proteins after reoxygenation. Proc. Natl. Acad. Sci. USA. 81:4843–4847.

    Google Scholar 

  28. Mestril, R., Chi, S-H., Sayen, M. R., and Dillmann, W. H. 1994. Isolation of a novel inducible rat heat shock protein(HSP70) gene and its expression during ischaemia/hypoxia and heat shock. Biochem. J. 298:561–569.

    Google Scholar 

  29. Kourembanas, S., Hanna, R. L., and Faller, D. V. 1990. Oxygen tension regulates the expression of the platelet-derived growth factor-B chain gene in human endothelial cells. J. Clin. Invest. 86:670–674.

    Google Scholar 

  30. Karakurum, M., Shreeniwas, R., Chen, J., Pinsky, D., Yan, S-D., Anderson, M., Sunovichi, K., Major, J., Hamilton, T., Kuwabara, K., Rot, A., Nowygrod, R., and Stern D. 1994. Hypoxic induction of interleukin-8 gene expression in human endothelial cell lines. J. Clin. Invest. 93:1564–1570.

    Google Scholar 

  31. Ghezzi, P., Dinarello, C. A., Bianchi, M., and Rosandich, M. E. 1991. Hypoxia increases production of interleukin-1 and tumor necrosis factor by human mononuclear cells. Cytokine 3:189–194.

    Google Scholar 

  32. West, M. A., Li, M. H., Seatter, S. C., and Bubrick, M. P. 1994. Pre-exposure to hypoxia or septic stimuli differentially regulates endotoxin release of tumor necrosis factor, interleukin-6, interleukin-1, prostaglandin E2, nitric oxide, and superoxide by macrophages. J. Trauma 37:82–90.

    Google Scholar 

  33. Brogi, E., Wu, T., Namiki, A., and Isner, J. M. 1994. Indirect angiogenic cytokines upregulate VEGF and bFGF gene expression in vascular smooth muscle cells, whereas hypoxia upregulates VEGF expression only. Circulation 90:649–652.

    Google Scholar 

  34. Shweiki, D., Itin, A., Soffer, D., and Keshet, E. 1992. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359:843–845.

    Google Scholar 

  35. Albina, J. E., Hanry, W. L., Mastrofrancesco, B., Martin, B-A., and Reichner, J. S. 1995. Macrophage activation by culture in an anoxic environment. J. Immunol. 155:4391–4396.

    Google Scholar 

  36. Melillo, G., Musso, T., Sica, A., Taylor, L. S., Cox, G. W., and Varesio, L. 1995. A hypoxia-responsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promotor. J. Exp. Med. 182:1683–1693.

    Google Scholar 

  37. Mirochnitchenko, O., and Inouye, M. 1996. Effect of overexpression of human Cu,Zn superoxide dismutase in transgenic mice on macrophage functions. J. Immunol. 156:1578–1586.

    Google Scholar 

  38. Crawford, D. W., and Blankenhorn, D. H. 1991. Arterial wall oxygenation, oxyradicals, and atherosclerosis. Atherosclerosis 89:97–108.

    Google Scholar 

  39. Mandel, P., Poirel, G., and Simard-Duquesne, N. 1966. Oxygen uptake of normal and atherosclerotic rabbit aortae in mediums of hyperlipaemic sera and plasmas. J. Atheroscler. Res. 6:463–466.

    Google Scholar 

  40. Brown, M. S., Ho, Y. K., and Goldstein, J. L. 1980. The cholesteryl ester cycle in macrophage foam cells. J. Biol. Chem. 255:9344–9352.

    Google Scholar 

  41. Cozzi, P. J., Lyon, R. T., Davis, H. R., Sylora, J., Glagov, S., and Zarins, C. K. 1988. Aortic wall metabolism in relation to susceptibility and resistance to experimental atherosclerosis. J. Vasc. Surg. 7:706–714.

    Google Scholar 

  42. Nagornev, V. A., and Maltseva, S. V. 1996. The phenotype of macrophages which are not transformed into foam cells in atherogenesis. Atherosclerosis 121:245–251.

    Google Scholar 

  43. Graeber, T. G., Osmaniah, C., Jacks, T., Housman, D. E., Koch, C. J., Lowe, S. W., and Giaccia, A. J. 1996. Hypoxia mediated selection of cells with diminished apoptotic potential in solid tumors. Nature 379:88–91.

    Google Scholar 

  44. Uemura, Y. 1990. Selective sparing of NADPH-diaphorase-somatostatin-neuropeptide Y neurons in ischemic gerbil striatum. Ann. Neurol. 27:620–625.

    Google Scholar 

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Yun, J.K., McCormick, T.S., Judware, R. et al. Cellular Adaptive Responses to Low Oxygen Tension: Apoptosis and Resistance. Neurochem Res 22, 517–521 (1997). https://doi.org/10.1023/A:1027328314968

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