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    SUR1-TRPM4 channel activation and phasic secretion of MMP-9 induced by tPA in brain endothelial cells

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    Author
    Gerzanich, V.
    Kwon, M.S.
    Woo, S.K.
    Date
    2018
    Journal
    PLoS ONE
    Publisher
    Public Library of Science
    Type
    Article
    
    Metadata
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    See at
    https://dx.doi.org/10.1371/journal.pone.0195526
    Abstract
    Background Hemorrhagic transformation is a major complication of ischemic stroke, is linked to matrix metalloproteinase-9 (MMP-9), and is exacerbated by tissue plasminogen activator (tPA). Cerebral ischemia/reperfusion is characterized by SUR1-TRPM4 (sulfonylurea receptor 1-transient receptor potential melastatin 4) channel upregulation in microvascular endothelium. In humans and rodents with cerebral ischemia/reperfusion (I/R), the SUR1 antagonist, glibenclamide, reduces hemorrhagic transformation and plasma MMP-9, but the mechanism is unknown. We hypothesized that tPA induces protease activated receptor 1 (PAR1)-mediated, Ca 2+ -dependent phasic secretion of MMP-9 from activated brain endothelium, and that SUR1-TRPM4 is required for this process. Methods Cerebral I/R, of 2 and 4 hours duration, respectively, was obtained using conventional middle cerebral artery occlusion. Immunolabeling was used to quantify p65 nuclear translocation. Murine and human brain endothelial cells (BEC) were studied in vitro, without and with NF-?B activation, using immunoblot, zymography and ELISA, patch clamp electrophysiology, and calcium imaging. Genetic and pharmacological manipulations were used to identify signaling pathways. Results Cerebral I/R caused prominent nuclear translocation of p65 in microvascular endothelium. NF-?B-activation of BEC caused de novo expression of SUR1-TRPM4 channels. In NF-?B-activated BEC: (i) tPA caused opening of SUR1-TRPM4 channels in a plasmin-, PAR1-, TRPC3- and Ca 2+ -dependent manner; (ii) tPA caused PAR1-dependent secretion of MMP-9; (iii) tonic secretion of MMP-9 by activated BEC was not influenced by SUR1 inhibition; (iv) phasic secretion of MMP-9 induced by tPA or the PAR1-agonist, TFLLR, required functional SUR1-TRPM4 channels, with inhibition of SUR1 decreasing tPA-induced MMP-9 secretion. Conclusions tPA induces PAR1-mediated, SUR1-TRPM4-dependent, phasic secretion of MMP-9 from activated brain endothelium. Copyright 2018 Gerzanich et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
    Keyword
    sulfonylurea receptor 1—transient receptor potential melastatin 4
    brain endothelium
    ischemic stroke
    Matrix Metalloproteinase 9
    Tissue Plasminogen Activator
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85045013892&doi=10.1371%2fjournal.pone.0195526&partnerID=40&md5=b72b4e15bca8c148a8c9f860f9e01b26; http://hdl.handle.net/10713/9088
    ae974a485f413a2113503eed53cd6c53
    10.1371/journal.pone.0195526
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