Thromb Haemost 2008; 100(06): 1014-1020
DOI: 10.1160/TH08-04-0259
Theme Issue Article
Schattauer GmbH

Anti-apoptotic roles of plasminogen activator inhibitor-1 as a neurotrophic factor in the central nervous system

Shinji Soeda
1  Department of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan
,
Satoru Koyanagi
2  Pharmaceutics, Division of Clinical Pharmacy, Department of Medico-Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
,
Yukako Kuramoto
1  Department of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan
,
Masahiko Kimura
3  Medical Informatics and Research Units, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan
,
Masatoshi Oda
1  Department of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan
,
Tomohiro Kozako
1  Department of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan
,
Satoru Hayashida
1  Department of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan
,
Hiroshi Shimeno
1  Department of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan
› Author Affiliations
Financial support: This work was supported in part by a Grant-in-Aid for Scientific Research I from the Ministry of Education, Science, Sports and Culture of Japan and by funds from Central Research Institute of Fukuoka University and from MEXT HAITEKU (2002-6).
Further Information

Publication History

Received: 24 April 2008

Accepted after minor revision: 02 September 2008

Publication Date:
23 November 2017 (online)

Summary

Plasminogen activator inhibitor-1 (PAI-1), a member of the ser-pin gene family, is the primary inhibitor of urokinase-type and tissue-type PA s.PA I-1 plays an important role in the process of peripheral tissue remodeling and fibrinolysis through the regulation of PA activity. This serpin is also produced in brain tissues and may regulate the neural protease sequence in the central nervous system (CNS), as it does in peripheral tissues. In fact, PA I-1 mRNA is up-regulated in mouse brain after stroke.The serpin activity of PA I-1 helps to prevent tissue-type PA -induced neuron death.However, we have previously found that PAI-1 has a novel biological function in the CNS: the contribution to survival of neurites on neurons. In neuronally differentiated rat pheochromocytoma (PC-12) cells, a deficiency of PA I-1 in vitro caused a significant reduction in Bcl-2 and Bcl-XL mRNAs and an increase in Bcl-XS and Bax mRNAs.The change in the balance between mRNA expressions of the anti- and pro-apoptotic Bcl-2 family proteins promoted the apoptotic sequence: cas-pase-3 activation, cytochrome c release from mitochondria and DNA fragmentation. Our results indicate that PA I-1 has an antiapoptotic role in neurons.PAI-1 prevented the disintegration of the formed neuronal networks by maintaining or promoting neuroprotective signaling through the MAPK/ ERK pathway, suggesting that the neuroprotective effect of PAI-1 is independent of its action as a protease inhibitor. This review discusses the neuroprotective effects of PA I-1 in vitro, together with the relevant data from other laboratories. Special emphasis is placed on its action on PC-12 cells.