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

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Serveur académique Lausannois

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info:eu-repo/semantics/altIdentifier/doi/10.1080/15548627.2021.1973339

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info:eu-repo/semantics/altIdentifier/pmid/34520334

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info:eu-repo/semantics/altIdentifier/urn/urn:nbn:ch:serval-BIB_92B2E7EE737F0

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Serveur Académique Lausannois

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Université de Lausanne et CHUV

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info:eu-repo/semantics/openAccess , CC BY 4.0 , https://creativecommons.org/licenses/by/4.0/

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Autophagy; Brain Ischemia/drug therapy; Glucose/pharmacology; Humans; Hypoxia; Insulin-Like Growth Factor Binding Protein 3/metabolism; Insulin-Like Growth Factor Binding Protein 3/pharmacology; Insulin-Like Growth Factor I/metabolism; Mechanistic Target of Rapamycin Complex 1/metabolism; Oxygen/pharmacology; Phosphatidylinositol 3-Kinases/metabolism; Proto-Oncogene Proteins c-akt/metabolism; Signal Transduction; Stroke/drug therapy; TOR Serine-Threonine Kinases/metabolism; Thrombolytic Therapy; Tissue Plasminogen Activator/metabolism; Tissue Plasminogen Activator/pharmacology; IGF1R; IGFBP3; LC3; MTORC1; SQSTM1/p62; stroke

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Nonsuppressible insulinlike activity Insulin-like growth factor Sulfation factor Thymidine factor Sulphation factor

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A.M. Thiebaut et al., « Thrombolysis by PLAT/tPA increases serum free IGF1 leading to a decrease of deleterious autophagy following brain ischemia. », Serveur académique Lausannois, ID : 10.1080/15548627.2021.1973339

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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 reox : 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.

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