Biphasic regulation of tissue plasminogen activator activity in ischemic rat brain and in cultured neural cells: Essential role of astrocyte-derived plasminogen activator inhibitor-1

Ji Woon Kim, Sung Hoon Lee, Hyun Myung Ko, Kyoung Ja Kwon, Kyu Suk Cho, Chang Soon Choi, Jin Hee Park, Hahn Young Kim, Jongmin Lee, Seol Heui Han, Louis J. Ignarro, Jae Hoon Cheong, Won Ki Kim, Chan Young Shin

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24 Citations (Scopus)

Abstract

In brain, the serine protease tissue plasminogen activator (tPA) and its endogenous inhibitor plasminogen activator inhibitor-1 (PAI-1) have been implicated in the regulation of various neurophysiological and pathological responses. In this study, we investigated the differential role of neurons and astrocytes in the regulation of tPA/PAI-1 activity in ischemic brain. The activity of tPA peaked transiently and then decreased in cortex and striatum along with delayed induction of PAI-1 in the inflammatory stage after MCAO/reperfusion injury. In cultured primary cells, glutamate stimulation increased tPA activity in neurons but not in other cells such as microglia and astrocytes. With LPS stimulation, a model of neuroinflammatory insults, robust PAI-1 induction was observed in astrocytes but not in neurons and microglia. The upregulation of PAI-1 by LPS in astrocytes was also verified by RT-PCR analysis as well as PAI-1 promoter reporter assay. Lastly, we checked the effects of hypoxia on tPA/PAI-1 activity. Hypoxia increased tPA release from neurons without effects on microglia, while the activity of tPA in astrocyte was decreased consistent with increased PAI-1 activity in astrocyte. Taken together, the results from the present study suggest that neurons are the major source of tPA and that the glutamate-induced stimulated release is mainly governed by neurons in the acute phase. In contrast, the massive up-regulation of PAI-1 in astrocytes during subchronic and chronic inflammatory conditions, leads to decreased tPA activity in the later stages of MCAO. Differential regulation of tPA and PAI-1 in neurons, astrocytes and microglia suggest more attention is required to understand the role of local tPA activity in the vicinity of individual cell types.

Original languageEnglish
Pages (from-to)423-433
Number of pages11
JournalNeurochemistry International
Volume58
Issue number3
DOIs
Publication statusPublished - 2011 Feb

Keywords

  • Astrocytes
  • Biphasic
  • LPS
  • MCAO
  • PAI-1
  • tPA

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology

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    Kim, J. W., Lee, S. H., Ko, H. M., Kwon, K. J., Cho, K. S., Choi, C. S., Park, J. H., Kim, H. Y., Lee, J., Han, S. H., Ignarro, L. J., Cheong, J. H., Kim, W. K., & Shin, C. Y. (2011). Biphasic regulation of tissue plasminogen activator activity in ischemic rat brain and in cultured neural cells: Essential role of astrocyte-derived plasminogen activator inhibitor-1. Neurochemistry International, 58(3), 423-433. https://doi.org/10.1016/j.neuint.2010.12.020