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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.
Neurochem Int. 2011 Feb; 58(3):423-33.NI

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.

Authors+Show Affiliations

Department of Pharmacology, Research Institute of Medical Sciences and Institute of Functional Genomics, Konkuk University, Seoul, Republic of Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21193004

Citation

Kim, Ji Woon, et al. "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, vol. 58, no. 3, 2011, pp. 423-33.
Kim JW, Lee SH, Ko HM, et al. 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. Neurochem Int. 2011;58(3):423-33.
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), 423-33. https://doi.org/10.1016/j.neuint.2010.12.020
Kim JW, et al. 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. Neurochem Int. 2011;58(3):423-33. PubMed PMID: 21193004.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Kim,Ji Woon, AU - Lee,Sung Hoon, AU - Ko,Hyun Myung, AU - Kwon,Kyoung Ja, AU - Cho,Kyu Suk, AU - Choi,Chang Soon, AU - Park,Jin-Hee, AU - Kim,Hahn Young, AU - Lee,Jongmin, AU - Han,Seol-Heui, AU - Ignarro,Louis J, AU - Cheong,Jae Hoon, AU - Kim,Won-Ki, AU - Shin,Chan Young, Y1 - 2010/12/28/ PY - 2010/10/08/received PY - 2010/12/21/revised PY - 2010/12/21/accepted PY - 2011/1/4/entrez PY - 2011/1/5/pubmed PY - 2011/12/28/medline SP - 423 EP - 33 JF - Neurochemistry international JO - Neurochem Int VL - 58 IS - 3 N2 - 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. SN - 1872-9754 UR - https://www.unboundmedicine.com/medline/citation/21193004/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0197-0186(10)00390-6 DB - PRIME DP - Unbound Medicine ER -