PAR-1 is a novel mechano-sensor transducing laminar flow-mediated endothelial signaling
Recent studies have indicated that protease-activated receptor-1 (PAR-1) is involved in cytoprotective and anti-inflammatory responses in endothelial cells (ECs). However, the role of PAR-1 in laminar flow-mediated atheroprotective responses remains unknown. Herein, we investigated whether PAR-1 reg...
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| description | Recent studies have indicated that protease-activated receptor-1 (PAR-1) is involved in cytoprotective and anti-inflammatory responses in endothelial cells (ECs). However, the role of PAR-1 in laminar flow-mediated atheroprotective responses remains unknown. Herein, we investigated whether PAR-1 regulates laminar flow-mediated mechanotransduction in ECs. Confocal analysis showed that PAR-1 was internalized into early endosomes in response to laminar flow. In addition, flow cytometry analysis showed that cell surface expression of PAR-1 was reduced by laminar flow, suggesting that PAR-1 was activated in response to laminar flow. Depletion of PAR-1 using human PAR-1 siRNA inhibited unidirectional laminar flow-mediated actin stress fiber formation and cellular alignment as well as atheroprotective gene expressions in HUVECs. Moreover, PAR-1 knockdown inhibited laminar flow-stimulated eNOS phosphorylation, and inhibited the phosphorylations of Src, AMPK, ERK5 and HDAC5. Furthermore, PAR-1 depletion inhibited laminar flow-mediated anti-inflammatory responses as demonstrated by reduced TNFα-induced VCAM-1 expression and by monocyte adhesion to HUVECs, and prevented laminar flow-mediated anti-apoptotic response. An investigation of the role of PAR-1 in vasomotor modulation using mouse aortic rings revealed that acetylcholine-induced vasorelaxation was diminished in PAR-1 deficient mice compared to littermate controls. Taken together, these findings suggest that PAR-1 be viewed as a novel pharmacologic target for the treatment of vascular diseases, including atherosclerosis. |
| doi_str_mv | 10.1038/s41598-018-33222-3 |
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| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6181929</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2119918279</sourcerecordid><originalsourceid>FETCH-LOGICAL-c577t-60a22f5fd0edb74db4a9038ca611202ce05929c8090639fe5dabf68675c394f73</originalsourceid><addsrcrecordid>eNp9kU1rFTEUhoMotlz7B1xIwI2baE4ymUk2Qil-QUERxWXIzZy5NyWT1GSm4r837a21ujCLfHCe8-Y9vIQ8Bf4SuNSvagfKaMZBMymFEEw-IMeCd4qJ9nx4735ETmq94G0pYTowj8mR5BI413BMvn06_cyAhkodTfkKI53R713KrGKqudCluFTH1Ye0o9HNIblCp5h_sBnH4BYcKaYxL3uMwUVawy652Ngn5NHkYsWT23NDvr598-XsPTv_-O7D2ek582oYFtZzJ8SkppHjuB26cds506bzrgcQXHjkygjjNTe8l2ZCNbrt1Ot-UF6abhrkhrw-6F6u2-bIY2qGo70sYXblp80u2L8rKeztLl_ZHjQ06Sbw4lag5O8r1sXOoXqM0SXMa7UCwBjQYrhGn_-DXuS1tHlvKC0H2StolDhQvuRaC053ZoDb6-jsITrborM30bV9Q57dH-Ou5XdQDZAHoLZS2mH58_d_ZH8B4WykOg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2118373651</pqid></control><display><type>article</type><title>PAR-1 is a novel mechano-sensor transducing laminar flow-mediated endothelial signaling</title><source>Nature Free</source><source>DOAJ Directory of Open Access Journals</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><source>Free Full-Text Journals in Chemistry</source><source>Springer Nature OA Free Journals</source><creator>Kim, Suji ; Han, Jung-Hwa ; Nam, Dae-Hwan ; Kim, Geun-Young ; Lim, Jae Hyang ; Kim, Jae-Ryong ; Woo, Chang-Hoon</creator><creatorcontrib>Kim, Suji ; Han, Jung-Hwa ; Nam, Dae-Hwan ; Kim, Geun-Young ; Lim, Jae Hyang ; Kim, Jae-Ryong ; Woo, Chang-Hoon</creatorcontrib><description>Recent studies have indicated that protease-activated receptor-1 (PAR-1) is involved in cytoprotective and anti-inflammatory responses in endothelial cells (ECs). However, the role of PAR-1 in laminar flow-mediated atheroprotective responses remains unknown. Herein, we investigated whether PAR-1 regulates laminar flow-mediated mechanotransduction in ECs. Confocal analysis showed that PAR-1 was internalized into early endosomes in response to laminar flow. In addition, flow cytometry analysis showed that cell surface expression of PAR-1 was reduced by laminar flow, suggesting that PAR-1 was activated in response to laminar flow. Depletion of PAR-1 using human PAR-1 siRNA inhibited unidirectional laminar flow-mediated actin stress fiber formation and cellular alignment as well as atheroprotective gene expressions in HUVECs. Moreover, PAR-1 knockdown inhibited laminar flow-stimulated eNOS phosphorylation, and inhibited the phosphorylations of Src, AMPK, ERK5 and HDAC5. Furthermore, PAR-1 depletion inhibited laminar flow-mediated anti-inflammatory responses as demonstrated by reduced TNFα-induced VCAM-1 expression and by monocyte adhesion to HUVECs, and prevented laminar flow-mediated anti-apoptotic response. An investigation of the role of PAR-1 in vasomotor modulation using mouse aortic rings revealed that acetylcholine-induced vasorelaxation was diminished in PAR-1 deficient mice compared to littermate controls. Taken together, these findings suggest that PAR-1 be viewed as a novel pharmacologic target for the treatment of vascular diseases, including atherosclerosis.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-018-33222-3</identifier><identifier>PMID: 30310081</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/106 ; 13/31 ; 13/89 ; 13/95 ; 14/19 ; 14/63 ; 631/80/86/2366 ; 692/4017 ; Acetylcholine ; Actin ; Aorta ; Apoptosis ; Arteriosclerosis ; Cell surface ; Endosomes ; Endothelial cells ; Flow cytometry ; Humanities and Social Sciences ; Inflammation ; Mechanotransduction ; Monocytes ; multidisciplinary ; Phosphorylation ; Proteinase-activated receptor 1 ; Rodents ; Science ; Science (multidisciplinary) ; siRNA ; Tumor necrosis factor-α ; Vascular cell adhesion molecule 1 ; Vascular diseases ; Vasodilation</subject><ispartof>Scientific reports, 2018-10, Vol.8 (1), p.15172-14, Article 15172</ispartof><rights>The Author(s) 2018</rights><rights>2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c577t-60a22f5fd0edb74db4a9038ca611202ce05929c8090639fe5dabf68675c394f73</citedby><cites>FETCH-LOGICAL-c577t-60a22f5fd0edb74db4a9038ca611202ce05929c8090639fe5dabf68675c394f73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6181929/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6181929/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,41096,42165,51551,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30310081$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kim, Suji</creatorcontrib><creatorcontrib>Han, Jung-Hwa</creatorcontrib><creatorcontrib>Nam, Dae-Hwan</creatorcontrib><creatorcontrib>Kim, Geun-Young</creatorcontrib><creatorcontrib>Lim, Jae Hyang</creatorcontrib><creatorcontrib>Kim, Jae-Ryong</creatorcontrib><creatorcontrib>Woo, Chang-Hoon</creatorcontrib><title>PAR-1 is a novel mechano-sensor transducing laminar flow-mediated endothelial signaling</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Recent studies have indicated that protease-activated receptor-1 (PAR-1) is involved in cytoprotective and anti-inflammatory responses in endothelial cells (ECs). However, the role of PAR-1 in laminar flow-mediated atheroprotective responses remains unknown. Herein, we investigated whether PAR-1 regulates laminar flow-mediated mechanotransduction in ECs. Confocal analysis showed that PAR-1 was internalized into early endosomes in response to laminar flow. In addition, flow cytometry analysis showed that cell surface expression of PAR-1 was reduced by laminar flow, suggesting that PAR-1 was activated in response to laminar flow. Depletion of PAR-1 using human PAR-1 siRNA inhibited unidirectional laminar flow-mediated actin stress fiber formation and cellular alignment as well as atheroprotective gene expressions in HUVECs. Moreover, PAR-1 knockdown inhibited laminar flow-stimulated eNOS phosphorylation, and inhibited the phosphorylations of Src, AMPK, ERK5 and HDAC5. Furthermore, PAR-1 depletion inhibited laminar flow-mediated anti-inflammatory responses as demonstrated by reduced TNFα-induced VCAM-1 expression and by monocyte adhesion to HUVECs, and prevented laminar flow-mediated anti-apoptotic response. An investigation of the role of PAR-1 in vasomotor modulation using mouse aortic rings revealed that acetylcholine-induced vasorelaxation was diminished in PAR-1 deficient mice compared to littermate controls. Taken together, these findings suggest that PAR-1 be viewed as a novel pharmacologic target for the treatment of vascular diseases, including atherosclerosis.</description><subject>13/106</subject><subject>13/31</subject><subject>13/89</subject><subject>13/95</subject><subject>14/19</subject><subject>14/63</subject><subject>631/80/86/2366</subject><subject>692/4017</subject><subject>Acetylcholine</subject><subject>Actin</subject><subject>Aorta</subject><subject>Apoptosis</subject><subject>Arteriosclerosis</subject><subject>Cell surface</subject><subject>Endosomes</subject><subject>Endothelial cells</subject><subject>Flow cytometry</subject><subject>Humanities and Social Sciences</subject><subject>Inflammation</subject><subject>Mechanotransduction</subject><subject>Monocytes</subject><subject>multidisciplinary</subject><subject>Phosphorylation</subject><subject>Proteinase-activated receptor 1</subject><subject>Rodents</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>siRNA</subject><subject>Tumor necrosis factor-α</subject><subject>Vascular cell adhesion molecule 1</subject><subject>Vascular diseases</subject><subject>Vasodilation</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>BENPR</sourceid><recordid>eNp9kU1rFTEUhoMotlz7B1xIwI2baE4ymUk2Qil-QUERxWXIzZy5NyWT1GSm4r837a21ujCLfHCe8-Y9vIQ8Bf4SuNSvagfKaMZBMymFEEw-IMeCd4qJ9nx4735ETmq94G0pYTowj8mR5BI413BMvn06_cyAhkodTfkKI53R713KrGKqudCluFTH1Ye0o9HNIblCp5h_sBnH4BYcKaYxL3uMwUVawy652Ngn5NHkYsWT23NDvr598-XsPTv_-O7D2ek582oYFtZzJ8SkppHjuB26cds506bzrgcQXHjkygjjNTe8l2ZCNbrt1Ot-UF6abhrkhrw-6F6u2-bIY2qGo70sYXblp80u2L8rKeztLl_ZHjQ06Sbw4lag5O8r1sXOoXqM0SXMa7UCwBjQYrhGn_-DXuS1tHlvKC0H2StolDhQvuRaC053ZoDb6-jsITrborM30bV9Q57dH-Ou5XdQDZAHoLZS2mH58_d_ZH8B4WykOg</recordid><startdate>20181011</startdate><enddate>20181011</enddate><creator>Kim, Suji</creator><creator>Han, Jung-Hwa</creator><creator>Nam, Dae-Hwan</creator><creator>Kim, Geun-Young</creator><creator>Lim, Jae Hyang</creator><creator>Kim, Jae-Ryong</creator><creator>Woo, Chang-Hoon</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</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>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20181011</creationdate><title>PAR-1 is a novel mechano-sensor transducing laminar flow-mediated endothelial signaling</title><author>Kim, Suji ; 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However, the role of PAR-1 in laminar flow-mediated atheroprotective responses remains unknown. Herein, we investigated whether PAR-1 regulates laminar flow-mediated mechanotransduction in ECs. Confocal analysis showed that PAR-1 was internalized into early endosomes in response to laminar flow. In addition, flow cytometry analysis showed that cell surface expression of PAR-1 was reduced by laminar flow, suggesting that PAR-1 was activated in response to laminar flow. Depletion of PAR-1 using human PAR-1 siRNA inhibited unidirectional laminar flow-mediated actin stress fiber formation and cellular alignment as well as atheroprotective gene expressions in HUVECs. Moreover, PAR-1 knockdown inhibited laminar flow-stimulated eNOS phosphorylation, and inhibited the phosphorylations of Src, AMPK, ERK5 and HDAC5. Furthermore, PAR-1 depletion inhibited laminar flow-mediated anti-inflammatory responses as demonstrated by reduced TNFα-induced VCAM-1 expression and by monocyte adhesion to HUVECs, and prevented laminar flow-mediated anti-apoptotic response. An investigation of the role of PAR-1 in vasomotor modulation using mouse aortic rings revealed that acetylcholine-induced vasorelaxation was diminished in PAR-1 deficient mice compared to littermate controls. Taken together, these findings suggest that PAR-1 be viewed as a novel pharmacologic target for the treatment of vascular diseases, including atherosclerosis.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>30310081</pmid><doi>10.1038/s41598-018-33222-3</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 13/106 13/31 13/89 13/95 14/19 14/63 631/80/86/2366 692/4017 Acetylcholine Actin Aorta Apoptosis Arteriosclerosis Cell surface Endosomes Endothelial cells Flow cytometry Humanities and Social Sciences Inflammation Mechanotransduction Monocytes multidisciplinary Phosphorylation Proteinase-activated receptor 1 Rodents Science Science (multidisciplinary) siRNA Tumor necrosis factor-α Vascular cell adhesion molecule 1 Vascular diseases Vasodilation |
| title | PAR-1 is a novel mechano-sensor transducing laminar flow-mediated endothelial signaling |
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