Show simple item record

dc.contributor.authorGerzanich, V.
dc.contributor.authorKwon, M.S.
dc.contributor.authorWoo, S.K.
dc.date.accessioned2019-05-17T12:53:04Z
dc.date.available2019-05-17T12:53:04Z
dc.date.issued2018
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85045013892&doi=10.1371%2fjournal.pone.0195526&partnerID=40&md5=b72b4e15bca8c148a8c9f860f9e01b26
dc.identifier.urihttp://hdl.handle.net/10713/9088
dc.description.abstractBackground 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.en_US
dc.description.urihttps://dx.doi.org/10.1371/journal.pone.0195526en_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.ispartofPLoS ONE
dc.subjectsulfonylurea receptor 1—transient receptor potential melastatin 4en_US
dc.subjectbrain endotheliumen_US
dc.subjectischemic strokeen_US
dc.subject.meshMatrix Metalloproteinase 9en_US
dc.subject.meshTissue Plasminogen Activatoren_US
dc.titleSUR1-TRPM4 channel activation and phasic secretion of MMP-9 induced by tPA in brain endothelial cellsen_US
dc.typeArticleen_US
dc.identifier.doi10.1371/journal.pone.0195526
dc.identifier.pmid29617457


This item appears in the following Collection(s)

Show simple item record