Role of claudin-5 in the attenuation of murine acute lung injury by simvastatin
The statins are now recognized to have pleiotropic properties, including augmentation of endothelial barrier function. To explore the mechanisms involved, we investigated the effect of simvastatin on endothelial cell (EC) tight junctions. Western blotting of human pulmonary artery ECs treated with s...
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| Veröffentlicht in: | American journal of respiratory cell and molecular biology 2014-02, Vol.50 (2), p.328-336 |
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| description | The statins are now recognized to have pleiotropic properties, including augmentation of endothelial barrier function. To explore the mechanisms involved, we investigated the effect of simvastatin on endothelial cell (EC) tight junctions. Western blotting of human pulmonary artery ECs treated with simvastatin (5 μM) confirmed a significant time-dependent increase (16-48 h) in claudin-5 protein expression compared with controls, without detectable alterations in zonula occludens-1 or occludin. These effects were associated with membrane translocation of VE-cadherin, whereas translocation of vascular endothelial cadherin (VE-cadherin; silencing RNA) inhibited simvastatin-induced claudin-5 up-regulation. Moreover, simvastatin treatment of ECs induced increased phosphorylation of both FoxO1 and β-catenin, transcriptional regulators of claudin-5 expression mediated by VE-cadherin. Subsequently, we found no effect of claudin-5 silencing on EC barrier protection by simvastatin in response to thrombin stimulation, as measured by either transendothelial electrical resistance or by EC monolayer flux of FITC-dextran (2,000 kD). However, silencing of claudin-5 did significantly attenuate simvastatin-mediated EC barrier protection in response to thrombin, as measured by monolayer flux of sodium fluorescein (376 Da). Finally, employing a murine model of LPS-induced acute lung injury, there was no effect of claudin-5 silencing in vivo (intratracheal injection) on bronchoalveolar lavage fluid protein or cell counts, but LPS-induced lung tissue extravasation of the small molecular weight markers, sodium fluorescein and Hochst stain (562 Da), were significantly increased in claudin-5-silenced animals compared with simvastatin-treated control animals. These findings implicate a distinct mechanism underlying size-selective endothelial barrier-protective properties of statins, and may ultimately lead to new novel therapeutic targets for patients with acute lung injury. |
| doi_str_mv | 10.1165/rcmb.2013-0058oc |
| format | Article |
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To explore the mechanisms involved, we investigated the effect of simvastatin on endothelial cell (EC) tight junctions. Western blotting of human pulmonary artery ECs treated with simvastatin (5 μM) confirmed a significant time-dependent increase (16-48 h) in claudin-5 protein expression compared with controls, without detectable alterations in zonula occludens-1 or occludin. These effects were associated with membrane translocation of VE-cadherin, whereas translocation of vascular endothelial cadherin (VE-cadherin; silencing RNA) inhibited simvastatin-induced claudin-5 up-regulation. Moreover, simvastatin treatment of ECs induced increased phosphorylation of both FoxO1 and β-catenin, transcriptional regulators of claudin-5 expression mediated by VE-cadherin. Subsequently, we found no effect of claudin-5 silencing on EC barrier protection by simvastatin in response to thrombin stimulation, as measured by either transendothelial electrical resistance or by EC monolayer flux of FITC-dextran (2,000 kD). However, silencing of claudin-5 did significantly attenuate simvastatin-mediated EC barrier protection in response to thrombin, as measured by monolayer flux of sodium fluorescein (376 Da). Finally, employing a murine model of LPS-induced acute lung injury, there was no effect of claudin-5 silencing in vivo (intratracheal injection) on bronchoalveolar lavage fluid protein or cell counts, but LPS-induced lung tissue extravasation of the small molecular weight markers, sodium fluorescein and Hochst stain (562 Da), were significantly increased in claudin-5-silenced animals compared with simvastatin-treated control animals. These findings implicate a distinct mechanism underlying size-selective endothelial barrier-protective properties of statins, and may ultimately lead to new novel therapeutic targets for patients with acute lung injury.</description><identifier>ISSN: 1044-1549</identifier><identifier>EISSN: 1535-4989</identifier><identifier>DOI: 10.1165/rcmb.2013-0058oc</identifier><identifier>PMID: 24028293</identifier><language>eng</language><publisher>United States: American Thoracic Society</publisher><subject>Acute Lung Injury - metabolism ; Acute Lung Injury - therapy ; Animals ; beta Catenin - metabolism ; Capillary Permeability - physiology ; Cell culture ; Cells, Cultured ; Claudin-5 - genetics ; Claudin-5 - metabolism ; Disease Models, Animal ; Endothelial Cells - drug effects ; Endothelial Cells - metabolism ; Gene Expression Regulation - drug effects ; Gene Silencing - physiology ; Humans ; Kinases ; Lung - metabolism ; Mice ; Mice, Inbred C57BL ; Molecular weight ; Original Research ; Permeability ; Phosphorylation ; Proteins ; Pulmonary arteries ; Simvastatin - metabolism ; Simvastatin - pharmacology ; Statins ; Tight Junctions - drug effects ; Tight Junctions - metabolism</subject><ispartof>American journal of respiratory cell and molecular biology, 2014-02, Vol.50 (2), p.328-336</ispartof><rights>Copyright American Thoracic Society Feb 2014</rights><rights>Copyright © 2014 by the American Thoracic Society 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c523t-8da4bf01c7c8d071d7aa9e93b60830349c5f3d86fb4ee74735a7eaf276cec1c93</citedby><cites>FETCH-LOGICAL-c523t-8da4bf01c7c8d071d7aa9e93b60830349c5f3d86fb4ee74735a7eaf276cec1c93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24028293$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Weiguo</creatorcontrib><creatorcontrib>Sharma, Rajesh</creatorcontrib><creatorcontrib>Rizzo, Alicia N</creatorcontrib><creatorcontrib>Siegler, Jessica H</creatorcontrib><creatorcontrib>Garcia, Joe G N</creatorcontrib><creatorcontrib>Jacobson, Jeffrey R</creatorcontrib><title>Role of claudin-5 in the attenuation of murine acute lung injury by simvastatin</title><title>American journal of respiratory cell and molecular biology</title><addtitle>Am J Respir Cell Mol Biol</addtitle><description>The statins are now recognized to have pleiotropic properties, including augmentation of endothelial barrier function. To explore the mechanisms involved, we investigated the effect of simvastatin on endothelial cell (EC) tight junctions. Western blotting of human pulmonary artery ECs treated with simvastatin (5 μM) confirmed a significant time-dependent increase (16-48 h) in claudin-5 protein expression compared with controls, without detectable alterations in zonula occludens-1 or occludin. These effects were associated with membrane translocation of VE-cadherin, whereas translocation of vascular endothelial cadherin (VE-cadherin; silencing RNA) inhibited simvastatin-induced claudin-5 up-regulation. Moreover, simvastatin treatment of ECs induced increased phosphorylation of both FoxO1 and β-catenin, transcriptional regulators of claudin-5 expression mediated by VE-cadherin. Subsequently, we found no effect of claudin-5 silencing on EC barrier protection by simvastatin in response to thrombin stimulation, as measured by either transendothelial electrical resistance or by EC monolayer flux of FITC-dextran (2,000 kD). However, silencing of claudin-5 did significantly attenuate simvastatin-mediated EC barrier protection in response to thrombin, as measured by monolayer flux of sodium fluorescein (376 Da). Finally, employing a murine model of LPS-induced acute lung injury, there was no effect of claudin-5 silencing in vivo (intratracheal injection) on bronchoalveolar lavage fluid protein or cell counts, but LPS-induced lung tissue extravasation of the small molecular weight markers, sodium fluorescein and Hochst stain (562 Da), were significantly increased in claudin-5-silenced animals compared with simvastatin-treated control animals. These findings implicate a distinct mechanism underlying size-selective endothelial barrier-protective properties of statins, and may ultimately lead to new novel therapeutic targets for patients with acute lung injury.</description><subject>Acute Lung Injury - metabolism</subject><subject>Acute Lung Injury - therapy</subject><subject>Animals</subject><subject>beta Catenin - metabolism</subject><subject>Capillary Permeability - physiology</subject><subject>Cell culture</subject><subject>Cells, Cultured</subject><subject>Claudin-5 - genetics</subject><subject>Claudin-5 - metabolism</subject><subject>Disease Models, Animal</subject><subject>Endothelial Cells - drug effects</subject><subject>Endothelial Cells - metabolism</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Gene Silencing - physiology</subject><subject>Humans</subject><subject>Kinases</subject><subject>Lung - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Molecular weight</subject><subject>Original Research</subject><subject>Permeability</subject><subject>Phosphorylation</subject><subject>Proteins</subject><subject>Pulmonary arteries</subject><subject>Simvastatin - metabolism</subject><subject>Simvastatin - pharmacology</subject><subject>Statins</subject><subject>Tight Junctions - drug effects</subject><subject>Tight Junctions - metabolism</subject><issn>1044-1549</issn><issn>1535-4989</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNpdkclLxTAQh4Mo7ndPUvDipZq1TS6CPNxAeCB6Dmmaah5tolmE99-b4oJ6mjDzzY8MHwBHCJ4h1LDzoKfuDENEaggZ93oD7CJGWE0FF5vlDSmtEaNiB-zFuIIQYY7QNtjBFGKOBdkFywc_msoPlR5V7q2rWWVdlV5MpVIyLqtkvZvnUw7Wla7OyVRjds-FW-Wwrrp1Fe30rmIqrDsAW4Maozn8qvvg6frqcXFb3y9v7haX97VmmKSa94p2A0S61byHLepbpYQRpGsgJ5BQodlAet4MHTWmpS1hqjVqwG2jjUZakH1w8Zn7mrvJ9Nq4FNQoX4OdVFhLr6z8O3H2RT77d0kEgYI2JeD0KyD4t2xikpON2oyjcsbnKBHDQhDcCF7Qk3_oyufgynmFgiWOYzxT8JPSwccYzPDzGQTlbEvOtuRsS862louycvz7iJ-Fbz3kA0uHklQ</recordid><startdate>201402</startdate><enddate>201402</enddate><creator>Chen, Weiguo</creator><creator>Sharma, Rajesh</creator><creator>Rizzo, Alicia N</creator><creator>Siegler, Jessica H</creator><creator>Garcia, Joe G N</creator><creator>Jacobson, Jeffrey R</creator><general>American Thoracic Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8AF</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>S0X</scope><scope>5PM</scope></search><sort><creationdate>201402</creationdate><title>Role of claudin-5 in the attenuation of murine acute lung injury by simvastatin</title><author>Chen, Weiguo ; Sharma, Rajesh ; Rizzo, Alicia N ; Siegler, Jessica H ; Garcia, Joe G N ; Jacobson, Jeffrey R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c523t-8da4bf01c7c8d071d7aa9e93b60830349c5f3d86fb4ee74735a7eaf276cec1c93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Acute Lung Injury - metabolism</topic><topic>Acute Lung Injury - therapy</topic><topic>Animals</topic><topic>beta Catenin - metabolism</topic><topic>Capillary Permeability - physiology</topic><topic>Cell culture</topic><topic>Cells, Cultured</topic><topic>Claudin-5 - genetics</topic><topic>Claudin-5 - metabolism</topic><topic>Disease Models, Animal</topic><topic>Endothelial Cells - drug effects</topic><topic>Endothelial Cells - metabolism</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Gene Silencing - physiology</topic><topic>Humans</topic><topic>Kinases</topic><topic>Lung - metabolism</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Molecular weight</topic><topic>Original Research</topic><topic>Permeability</topic><topic>Phosphorylation</topic><topic>Proteins</topic><topic>Pulmonary arteries</topic><topic>Simvastatin - metabolism</topic><topic>Simvastatin - pharmacology</topic><topic>Statins</topic><topic>Tight Junctions - drug effects</topic><topic>Tight Junctions - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Weiguo</creatorcontrib><creatorcontrib>Sharma, Rajesh</creatorcontrib><creatorcontrib>Rizzo, Alicia N</creatorcontrib><creatorcontrib>Siegler, Jessica H</creatorcontrib><creatorcontrib>Garcia, Joe G N</creatorcontrib><creatorcontrib>Jacobson, Jeffrey R</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>SIRS Editorial</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>American journal of respiratory cell and molecular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Weiguo</au><au>Sharma, Rajesh</au><au>Rizzo, Alicia N</au><au>Siegler, Jessica H</au><au>Garcia, Joe G N</au><au>Jacobson, Jeffrey R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Role of claudin-5 in the attenuation of murine acute lung injury by simvastatin</atitle><jtitle>American journal of respiratory cell and molecular biology</jtitle><addtitle>Am J Respir Cell Mol Biol</addtitle><date>2014-02</date><risdate>2014</risdate><volume>50</volume><issue>2</issue><spage>328</spage><epage>336</epage><pages>328-336</pages><issn>1044-1549</issn><eissn>1535-4989</eissn><abstract>The statins are now recognized to have pleiotropic properties, including augmentation of endothelial barrier function. To explore the mechanisms involved, we investigated the effect of simvastatin on endothelial cell (EC) tight junctions. Western blotting of human pulmonary artery ECs treated with simvastatin (5 μM) confirmed a significant time-dependent increase (16-48 h) in claudin-5 protein expression compared with controls, without detectable alterations in zonula occludens-1 or occludin. These effects were associated with membrane translocation of VE-cadherin, whereas translocation of vascular endothelial cadherin (VE-cadherin; silencing RNA) inhibited simvastatin-induced claudin-5 up-regulation. Moreover, simvastatin treatment of ECs induced increased phosphorylation of both FoxO1 and β-catenin, transcriptional regulators of claudin-5 expression mediated by VE-cadherin. Subsequently, we found no effect of claudin-5 silencing on EC barrier protection by simvastatin in response to thrombin stimulation, as measured by either transendothelial electrical resistance or by EC monolayer flux of FITC-dextran (2,000 kD). However, silencing of claudin-5 did significantly attenuate simvastatin-mediated EC barrier protection in response to thrombin, as measured by monolayer flux of sodium fluorescein (376 Da). Finally, employing a murine model of LPS-induced acute lung injury, there was no effect of claudin-5 silencing in vivo (intratracheal injection) on bronchoalveolar lavage fluid protein or cell counts, but LPS-induced lung tissue extravasation of the small molecular weight markers, sodium fluorescein and Hochst stain (562 Da), were significantly increased in claudin-5-silenced animals compared with simvastatin-treated control animals. These findings implicate a distinct mechanism underlying size-selective endothelial barrier-protective properties of statins, and may ultimately lead to new novel therapeutic targets for patients with acute lung injury.</abstract><cop>United States</cop><pub>American Thoracic Society</pub><pmid>24028293</pmid><doi>10.1165/rcmb.2013-0058oc</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Journals@Ovid Complete; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Acute Lung Injury - metabolism Acute Lung Injury - therapy Animals beta Catenin - metabolism Capillary Permeability - physiology Cell culture Cells, Cultured Claudin-5 - genetics Claudin-5 - metabolism Disease Models, Animal Endothelial Cells - drug effects Endothelial Cells - metabolism Gene Expression Regulation - drug effects Gene Silencing - physiology Humans Kinases Lung - metabolism Mice Mice, Inbred C57BL Molecular weight Original Research Permeability Phosphorylation Proteins Pulmonary arteries Simvastatin - metabolism Simvastatin - pharmacology Statins Tight Junctions - drug effects Tight Junctions - metabolism |
| title | Role of claudin-5 in the attenuation of murine acute lung injury by simvastatin |
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