Thrombolysis by PLAT/tPA increases serum free IGF1 leading to a decrease of deleterious autophagy following brain ischemia.

Details

Serval ID
serval:BIB_92B2E7EE737F
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Thrombolysis by PLAT/tPA increases serum free IGF1 leading to a decrease of deleterious autophagy following brain ischemia.
Journal
Autophagy
Author(s)
Thiebaut A.M., Buendia I., Ginet V., Lemarchand E., Boudjadja M.B., Hommet Y., Lebouvier L., Lechevallier C., Maillasson M., Hedou E., Déglon N., Oury F., Rubio M., Montaner J., Puyal J., Vivien D., Roussel B.D.
ISSN
1554-8635 (Electronic)
ISSN-L
1554-8627
Publication state
Published
Issued date
14/09/2021
Peer-reviewed
Oui
Pages
1-21
Language
english
Notes
Publication types: Journal Article
Publication Status: aheadofprint
Abstract
Cerebral ischemia is a pathology involving a cascade of cellular mechanisms, leading to the deregulation of proteostasis, including macroautophagy/autophagy, and finally to neuronal death. If it is now accepted that cerebral ischemia induces autophagy, the effect of thrombolysis/energy recovery on proteostasis remains unknown. Here, we investigated the effect of thrombolysis by PLAT/tPA (plasminogen activator, tissue) on autophagy and neuronal death. In two in vitro models of hypoxia reperfusion and an in vivo model of thromboembolic stroke with thrombolysis by PLAT/tPA, we found that ischemia enhances neuronal deleterious autophagy. Interestingly, PLAT/tPA decreases autophagy to mediate neuroprotection by modulating the PI3K-AKT-MTOR pathways both in vitro and in vivo. We identified IGF1R (insulin-like growth factor I receptor; a tyrosine kinase receptor) as the effective receptor and showed in vitro, in vivo and in human stroke patients and that PLAT/tPA is able to degrade IGFBP3 (insulin-like growth factor binding protein 3) to increase IGF1 (insulin-like growth factor 1) bioavailability and thus IGF1R activation.Abbreviations: AKT/protein kinase B: thymoma viral proto-oncogene 1; EGFR: epidermal growth factor receptor; Hx: hypoxia; IGF1: insulin-like growth factor 1; IGF1R: insulin-like growth factor I receptor; IGFBP3: insulin-like growth factor binding protein 3; Ka: Kainate; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK/ERK: mitogen-activated protein kinase; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; OGD: oxygen and glucose deprivation; OGD <sub>reox</sub> : oxygen and glucose deprivation + reoxygentation; PepA: pepstatin A1; PI3K: phosphoinositide 3-kinase; PLAT/tPA: plasminogen activator, tissue; PPP: picropodophyllin; SCH77: SCH772984; ULK1: unc-51 like kinase 1; Wort: wortmannin.
Keywords
IGF1R, IGFBP3, LC3, MTORC1, SQSTM1/p62, stroke
Pubmed
Web of science
Create date
15/09/2021 14:32
Last modification date
05/10/2021 5:40
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