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dc.contributor.authorKovacs-Kasa, Anita
dc.contributor.authorGorshkov, Boris A.
dc.contributor.authorKim, Kyung-Mi
dc.contributor.authorKumar, Sanjiv
dc.contributor.authorBlack, Stephen M.
dc.contributor.authorFulton, David J.
dc.contributor.authorDimitropoulou, Christiana
dc.contributor.authorCatravas, John D.
dc.contributor.authorVerin, Alexander D.
dc.date.accessioned2017-03-01T23:39:12Z
dc.date.available2017-03-01T23:39:12Z
dc.date.issued2016-12-15
dc.identifier.citationThe protective role of MLCP-mediated ERM dephosphorylation in endotoxin-induced lung injury in vitro and in vivo 2016, 6:39018 Scientific Reportsen
dc.identifier.issn2045-2322
dc.identifier.doi10.1038/srep39018
dc.identifier.urihttp://hdl.handle.net/10150/622686
dc.description.abstractThe goal of this study was to investigate the role of MLC phosphatase (MLCP) in a LPS model of acute lung injury (ALI). We demonstrate that ectopic expression of a constitutively-active (C/A) MLCP regulatory subunit (MYPT1) attenuates the ability of LPS to increase endothelial (EC) permeability. Down-regulation of MYPT1 exacerbates LPS-induced expression of ICAM1 suggesting an anti-inflammatory role of MLCP. To determine whether MLCP contributes to LPS-induced ALI in vivo, we utilized a nanoparticle DNA delivery method to specifically target lung EC. Expression of a C/A MYPT1 reduced LPS-induced lung inflammation and vascular permeability. Further, increased expression of the CS1 beta (MLCP catalytic subunit) also reduced LPS-induced lung inflammation, whereas the inactive CS1 beta mutant increased vascular leak. We next examined the role of the cytoskeletal targets of MLCP, the ERM proteins (Ezrin/Radixin/Moesin), in mediating barrier dysfunction. LPS-induced increase in EC permeability was accompanied by PKC-mediated increase in ERM phosphorylation, which was more prominent in CS1 beta-depleted cells. Depletion of Moesin and Ezrin, but not Radixin attenuated LPS-induced increases in permeability. Further, delivery of a Moesin phospho-null mutant into murine lung endothelium attenuated LPS-induced lung inflammation and vascular leak suggesting that MLCP opposes LPS-induced ALI by mediating the dephosphorylation of Moesin and Ezrin.
dc.description.sponsorshipNIH [HL101902]en
dc.language.isoenen
dc.publisherNATURE PUBLISHING GROUPen
dc.relation.urlhttp://www.nature.com/articles/srep39018en
dc.rightsThis work is licensed under a Creative Commons Attribution 4.0 International License.en
dc.titleThe protective role of MLCP-mediated ERM dephosphorylation in endotoxin-induced lung injury in vitro and in vivoen
dc.typeArticleen
dc.contributor.departmentUniv Arizona, Ctr Lung Vasc Pathobiolen
dc.identifier.journalScientific Reportsen
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
refterms.dateFOA2018-09-11T17:47:14Z
html.description.abstractThe goal of this study was to investigate the role of MLC phosphatase (MLCP) in a LPS model of acute lung injury (ALI). We demonstrate that ectopic expression of a constitutively-active (C/A) MLCP regulatory subunit (MYPT1) attenuates the ability of LPS to increase endothelial (EC) permeability. Down-regulation of MYPT1 exacerbates LPS-induced expression of ICAM1 suggesting an anti-inflammatory role of MLCP. To determine whether MLCP contributes to LPS-induced ALI in vivo, we utilized a nanoparticle DNA delivery method to specifically target lung EC. Expression of a C/A MYPT1 reduced LPS-induced lung inflammation and vascular permeability. Further, increased expression of the CS1 beta (MLCP catalytic subunit) also reduced LPS-induced lung inflammation, whereas the inactive CS1 beta mutant increased vascular leak. We next examined the role of the cytoskeletal targets of MLCP, the ERM proteins (Ezrin/Radixin/Moesin), in mediating barrier dysfunction. LPS-induced increase in EC permeability was accompanied by PKC-mediated increase in ERM phosphorylation, which was more prominent in CS1 beta-depleted cells. Depletion of Moesin and Ezrin, but not Radixin attenuated LPS-induced increases in permeability. Further, delivery of a Moesin phospho-null mutant into murine lung endothelium attenuated LPS-induced lung inflammation and vascular leak suggesting that MLCP opposes LPS-induced ALI by mediating the dephosphorylation of Moesin and Ezrin.


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