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
- Authors
- Kim, Ji Woon; Lee, Sung Hoon; Ko, Hyun Myung; Kwon, Kyoung Ja; Cho, Kyu Sul; Choi, Chang Soon; Park, Jin-Hee; Kim, Hahn Young; Lee, Jongmin; Han, Seol-Heui; Ignarro, Louis J.; Cheong, Jae Hoon; Kim, Won-Ki; Shin, Chan Young
- Issue Date
- 2월-2011
- Publisher
- PERGAMON-ELSEVIER SCIENCE LTD
- Keywords
- tPA; PAI-1; MCAO; LPS; Astrocytes; Biphasic
- Citation
- NEUROCHEMISTRY INTERNATIONAL, v.58, no.3, pp.423 - 433
- Indexed
- SCIE
SCOPUS
- Journal Title
- NEUROCHEMISTRY INTERNATIONAL
- Volume
- 58
- Number
- 3
- Start Page
- 423
- End Page
- 433
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/113175
- DOI
- 10.1016/j.neuint.2010.12.020
- ISSN
- 0197-0186
- 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. (C) 2010 Elsevier Ltd. All rights reserved.
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