Smad3-dependent induction of plasminogen activator inhibitor-1 in astrocytes mediates neuroprotective activity of transforming growth factor-beta 1 against NMDA-induced necrosis.
The intravenous injection of the serine protease, tissue-type plasminogen activator (t-PA), has shown to benefit stroke patients by promoting early reperfusion. However, it has recently been suggested that t-PA activity, in the cerebral parenchyma, may also potentiate excitotoxic neuronal death. The present study has dealt with the role of the t-PA inhibitor, PAI-1, in the neuroprotective activity of the cytokine TGF-beta1 and focused on the transduction pathway involved in this effect. We demonstrated that PAI-1, produced by astrocytes, mediates the neuroprotective activity of TGF-beta 1 against N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity. This t-PA inhibitor, PAI-1, protected neurons against NMDA-induced neuronal death by modulating the NMDA-evoked calcium influx. Finally, we showed that the activation of the Smad3-dependent transduction pathway mediates the TGF-beta-induced up-regulation of PAI-1 and subsequent neuroprotection. Overall, this study underlines the critical role of the t-PA/PAI-1 axis in the regulation of glutamatergic neurotransmission.
Docagne
Fabian
F
Université de Caen, CNRS UMR 6551, Bd H. Becquerel, B.P. 5229, 14074 Caen Cedex, France.
Nicole
Olivier
O
Gabriel
Cecilia
C
Fernández-Monreal
Mónica
M
Lesné
Sylvain
S
Ali
Carine
C
Plawinski
Laurent
L
Carmeliet
Peter
P
MacKenzie
Eric T
ET
Buisson
Alain
A
Vivien
Denis
D
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005333:Fetus; D051379:Mice; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D009498:Neurotoxins / Q000037:antagonists & inhibitors*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011993:Recombinant Fusion Proteins; D051900:Smad3 Protein; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors / Q000627:therapeutic use / Q000633:toxicity; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
D004268:DNA-Binding Proteins; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D009498:Neurotoxins; D017395:Plasminogen Activator Inhibitor 1; D011993:Recombinant Fusion Proteins; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016202:N-Methylaspartate; D010959:Tissue Plasminogen Activator