title: 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.
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.affiliation: Department of Pharmacology, Research Institute of Medical Sciences and Institute of Functional Genomics, Konkuk University, Seoul, Republic of Korea.
authors.forename: Ji Woon
authors.initials: JW
authors.lastname: Kim
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Hyun Myung
authors.initials: HM
authors.lastname: Ko
authors.forename: Kyoung Ja
authors.initials: KJ
authors.lastname: Kwon
authors.forename: Kyu Suk
authors.initials: KS
authors.lastname: Cho
authors.forename: Chang Soon
authors.initials: CS
authors.lastname: Choi
authors.forename: Jin-Hee
authors.initials: JH
authors.lastname: Park
authors.forename: Hahn Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Jongmin
authors.initials: J
authors.lastname: Lee
authors.forename: Seol-Heui
authors.initials: SH
authors.lastname: Han
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Ignarro
authors.forename: Jae Hoon
authors.initials: JH
authors.lastname: Cheong
authors.forename: Won-Ki
authors.initials: WK
authors.lastname: Kim
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Shin
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000473:pathology*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008297:Male; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D010959:Tissue Plasminogen Activator