Dabigatran Abrogates Brain Endothelial Cell Permeability in Response to Thrombin
Atrial fibrillation (AF) increases the risk and severity of thromboembolic stroke. Generally, antithrombotic agents increase the hemorrhagic risk of thromboembolic stroke. However, significant reductions in thromboembolism and intracerebral hemorrhage have been shown with the antithrombin dabigatran...
Gespeichert in:
| Veröffentlicht in: | Journal of cerebral blood flow and metabolism 2015-06, Vol.35 (6), p.985-992 |
|---|---|
| Hauptverfasser: | , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 992 |
|---|---|
| container_issue | 6 |
| container_start_page | 985 |
| container_title | Journal of cerebral blood flow and metabolism |
| container_volume | 35 |
| creator | Hawkins, Brian Thomas Gu, Yu-Huan Izawa, Yoshikane del Zoppo, Gregory John |
| description | Atrial fibrillation (AF) increases the risk and severity of thromboembolic stroke. Generally, antithrombotic agents increase the hemorrhagic risk of thromboembolic stroke. However, significant reductions in thromboembolism and intracerebral hemorrhage have been shown with the antithrombin dabigatran compared with warfarin. As thrombin has been implicated in microvessel injury during cerebral ischemia, we hypothesized that dabigatran decreases the risk of intracerebral hemorrhage by direct inhibition of the thrombin-mediated increase in cerebral endothelial cell permeability. Primary murine brain endothelial cells (mBECs) were exposed to murine thrombin before measuring permeability to 4-kDa fluorescein isothiocyanate-dextran. Thrombin increased mBEC permeability in a concentration-dependent manner, without significant endothelial cell death. Pretreatment of mBECs with dabigatran completely abrogated the effect of thrombin on permeability. Neither the expressions of the endothelial cell β1-integrins nor the tight junction protein claudin-5 were affected by thrombin exposure. Oxygen-glucose deprivation (OGD) also increased permeability; this effect was abrogated by treatment with dabigatran, as was the additive effect of thrombin and OGD on permeability. Taken together, these results indicate that dabigatran could contribute to a lower risk of intracerebral hemorrhage during embolism-associated ischemia from AF by protection of the microvessel permeability barrier from local thrombin challenge. |
| doi_str_mv | 10.1038/jcbfm.2015.9 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4640263</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sage_id>10.1038_jcbfm.2015.9</sage_id><sourcerecordid>1684435685</sourcerecordid><originalsourceid>FETCH-LOGICAL-c615t-e85132999245f8aceb85a4c6515730f86c16f582367aab2594153c82a293d2643</originalsourceid><addsrcrecordid>eNqF0c1LHDEYB-Aglbq1vfVcBnqx4Gzz9WaSS0G3WgWhUix4C5lsZjfLTLJNZgv-9812ragIPSWQh1_eD4TeEzwlmMnPK9t2w5RiAlO1hyYEQNUNJuIVmmDakFo08vYAvcl5hTGWDOA1OqAghFKETtD1V9P6hRmTCdVJm2K5ulydJuNDdRbmcVy63pu-mrm-r65dGlzxvR_vqgJ-uLyOIbtqjNXNMsWh9eEt2u9Mn927-_MQ_Tw_u5ld1Fffv13OTq5qKwiMtZNAGFVKUQ6dNNa1Egy3Agg0DHdSWCI6kJSJxpiWguIEmJXUUMXmVHB2iL7sctebdnBz60Lpodfr5AeT7nQ0Xj99CX6pF_G35oJjKlgJOLoPSPHXxuVRDz7b0qYJLm6yJmWIvFHbGv5LheScgZBQ6MdndBU3KZRJbBVrgAgmijreKZtizsl1D3UTrLdb1X-3qrdb1arwD497fcD_1ljApx3IZuEe_fhS2B8Dcqp2</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1683751636</pqid></control><display><type>article</type><title>Dabigatran Abrogates Brain Endothelial Cell Permeability in Response to Thrombin</title><source>Access via SAGE</source><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><creator>Hawkins, Brian Thomas ; Gu, Yu-Huan ; Izawa, Yoshikane ; del Zoppo, Gregory John</creator><creatorcontrib>Hawkins, Brian Thomas ; Gu, Yu-Huan ; Izawa, Yoshikane ; del Zoppo, Gregory John</creatorcontrib><description>Atrial fibrillation (AF) increases the risk and severity of thromboembolic stroke. Generally, antithrombotic agents increase the hemorrhagic risk of thromboembolic stroke. However, significant reductions in thromboembolism and intracerebral hemorrhage have been shown with the antithrombin dabigatran compared with warfarin. As thrombin has been implicated in microvessel injury during cerebral ischemia, we hypothesized that dabigatran decreases the risk of intracerebral hemorrhage by direct inhibition of the thrombin-mediated increase in cerebral endothelial cell permeability. Primary murine brain endothelial cells (mBECs) were exposed to murine thrombin before measuring permeability to 4-kDa fluorescein isothiocyanate-dextran. Thrombin increased mBEC permeability in a concentration-dependent manner, without significant endothelial cell death. Pretreatment of mBECs with dabigatran completely abrogated the effect of thrombin on permeability. Neither the expressions of the endothelial cell β1-integrins nor the tight junction protein claudin-5 were affected by thrombin exposure. Oxygen-glucose deprivation (OGD) also increased permeability; this effect was abrogated by treatment with dabigatran, as was the additive effect of thrombin and OGD on permeability. Taken together, these results indicate that dabigatran could contribute to a lower risk of intracerebral hemorrhage during embolism-associated ischemia from AF by protection of the microvessel permeability barrier from local thrombin challenge.</description><identifier>ISSN: 0271-678X</identifier><identifier>EISSN: 1559-7016</identifier><identifier>DOI: 10.1038/jcbfm.2015.9</identifier><identifier>PMID: 25669912</identifier><language>eng</language><publisher>London, England: SAGE Publications</publisher><subject>Animals ; Antithrombins - pharmacology ; Benzimidazoles - pharmacology ; beta-Alanine - analogs & derivatives ; beta-Alanine - pharmacology ; Brain - cytology ; Brain - drug effects ; Brain - metabolism ; Cell Survival - drug effects ; Cells, Cultured ; Claudin-5 - analysis ; Dabigatran ; Endothelial Cells - cytology ; Endothelial Cells - drug effects ; Endothelial Cells - metabolism ; Glucose - metabolism ; Integrin beta1 - analysis ; Male ; Mice ; Mice, Inbred C57BL ; Original ; Oxygen - metabolism ; Permeability - drug effects ; Thrombin - metabolism</subject><ispartof>Journal of cerebral blood flow and metabolism, 2015-06, Vol.35 (6), p.985-992</ispartof><rights>2015 ISCBFM</rights><rights>Copyright Nature Publishing Group Jun 2015</rights><rights>Copyright © 2015 International Society for Cerebral Blood Flow & Metabolism, Inc. 2015 International Society for Cerebral Blood Flow & Metabolism, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c615t-e85132999245f8aceb85a4c6515730f86c16f582367aab2594153c82a293d2643</citedby><cites>FETCH-LOGICAL-c615t-e85132999245f8aceb85a4c6515730f86c16f582367aab2594153c82a293d2643</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/PMC4640263/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4640263/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,315,728,781,785,886,21824,27929,27930,43626,43627,53796,53798</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25669912$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hawkins, Brian Thomas</creatorcontrib><creatorcontrib>Gu, Yu-Huan</creatorcontrib><creatorcontrib>Izawa, Yoshikane</creatorcontrib><creatorcontrib>del Zoppo, Gregory John</creatorcontrib><title>Dabigatran Abrogates Brain Endothelial Cell Permeability in Response to Thrombin</title><title>Journal of cerebral blood flow and metabolism</title><addtitle>J Cereb Blood Flow Metab</addtitle><description>Atrial fibrillation (AF) increases the risk and severity of thromboembolic stroke. Generally, antithrombotic agents increase the hemorrhagic risk of thromboembolic stroke. However, significant reductions in thromboembolism and intracerebral hemorrhage have been shown with the antithrombin dabigatran compared with warfarin. As thrombin has been implicated in microvessel injury during cerebral ischemia, we hypothesized that dabigatran decreases the risk of intracerebral hemorrhage by direct inhibition of the thrombin-mediated increase in cerebral endothelial cell permeability. Primary murine brain endothelial cells (mBECs) were exposed to murine thrombin before measuring permeability to 4-kDa fluorescein isothiocyanate-dextran. Thrombin increased mBEC permeability in a concentration-dependent manner, without significant endothelial cell death. Pretreatment of mBECs with dabigatran completely abrogated the effect of thrombin on permeability. Neither the expressions of the endothelial cell β1-integrins nor the tight junction protein claudin-5 were affected by thrombin exposure. Oxygen-glucose deprivation (OGD) also increased permeability; this effect was abrogated by treatment with dabigatran, as was the additive effect of thrombin and OGD on permeability. Taken together, these results indicate that dabigatran could contribute to a lower risk of intracerebral hemorrhage during embolism-associated ischemia from AF by protection of the microvessel permeability barrier from local thrombin challenge.</description><subject>Animals</subject><subject>Antithrombins - pharmacology</subject><subject>Benzimidazoles - pharmacology</subject><subject>beta-Alanine - analogs & derivatives</subject><subject>beta-Alanine - pharmacology</subject><subject>Brain - cytology</subject><subject>Brain - drug effects</subject><subject>Brain - metabolism</subject><subject>Cell Survival - drug effects</subject><subject>Cells, Cultured</subject><subject>Claudin-5 - analysis</subject><subject>Dabigatran</subject><subject>Endothelial Cells - cytology</subject><subject>Endothelial Cells - drug effects</subject><subject>Endothelial Cells - metabolism</subject><subject>Glucose - metabolism</subject><subject>Integrin beta1 - analysis</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Original</subject><subject>Oxygen - metabolism</subject><subject>Permeability - drug effects</subject><subject>Thrombin - metabolism</subject><issn>0271-678X</issn><issn>1559-7016</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</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>eNqF0c1LHDEYB-Aglbq1vfVcBnqx4Gzz9WaSS0G3WgWhUix4C5lsZjfLTLJNZgv-9812ragIPSWQh1_eD4TeEzwlmMnPK9t2w5RiAlO1hyYEQNUNJuIVmmDakFo08vYAvcl5hTGWDOA1OqAghFKETtD1V9P6hRmTCdVJm2K5ulydJuNDdRbmcVy63pu-mrm-r65dGlzxvR_vqgJ-uLyOIbtqjNXNMsWh9eEt2u9Mn927-_MQ_Tw_u5ld1Fffv13OTq5qKwiMtZNAGFVKUQ6dNNa1Egy3Agg0DHdSWCI6kJSJxpiWguIEmJXUUMXmVHB2iL7sctebdnBz60Lpodfr5AeT7nQ0Xj99CX6pF_G35oJjKlgJOLoPSPHXxuVRDz7b0qYJLm6yJmWIvFHbGv5LheScgZBQ6MdndBU3KZRJbBVrgAgmijreKZtizsl1D3UTrLdb1X-3qrdb1arwD497fcD_1ljApx3IZuEe_fhS2B8Dcqp2</recordid><startdate>20150601</startdate><enddate>20150601</enddate><creator>Hawkins, Brian Thomas</creator><creator>Gu, Yu-Huan</creator><creator>Izawa, Yoshikane</creator><creator>del Zoppo, Gregory John</creator><general>SAGE Publications</general><general>Sage Publications Ltd</general><general>Nature Publishing Group</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>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</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>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>7TK</scope><scope>5PM</scope></search><sort><creationdate>20150601</creationdate><title>Dabigatran Abrogates Brain Endothelial Cell Permeability in Response to Thrombin</title><author>Hawkins, Brian Thomas ; Gu, Yu-Huan ; Izawa, Yoshikane ; del Zoppo, Gregory John</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c615t-e85132999245f8aceb85a4c6515730f86c16f582367aab2594153c82a293d2643</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Antithrombins - pharmacology</topic><topic>Benzimidazoles - pharmacology</topic><topic>beta-Alanine - analogs & derivatives</topic><topic>beta-Alanine - pharmacology</topic><topic>Brain - cytology</topic><topic>Brain - drug effects</topic><topic>Brain - metabolism</topic><topic>Cell Survival - drug effects</topic><topic>Cells, Cultured</topic><topic>Claudin-5 - analysis</topic><topic>Dabigatran</topic><topic>Endothelial Cells - cytology</topic><topic>Endothelial Cells - drug effects</topic><topic>Endothelial Cells - metabolism</topic><topic>Glucose - metabolism</topic><topic>Integrin beta1 - analysis</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Original</topic><topic>Oxygen - metabolism</topic><topic>Permeability - drug effects</topic><topic>Thrombin - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hawkins, Brian Thomas</creatorcontrib><creatorcontrib>Gu, Yu-Huan</creatorcontrib><creatorcontrib>Izawa, Yoshikane</creatorcontrib><creatorcontrib>del Zoppo, Gregory John</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>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>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>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>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>MEDLINE - Academic</collection><collection>Neurosciences Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of cerebral blood flow and metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hawkins, Brian Thomas</au><au>Gu, Yu-Huan</au><au>Izawa, Yoshikane</au><au>del Zoppo, Gregory John</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dabigatran Abrogates Brain Endothelial Cell Permeability in Response to Thrombin</atitle><jtitle>Journal of cerebral blood flow and metabolism</jtitle><addtitle>J Cereb Blood Flow Metab</addtitle><date>2015-06-01</date><risdate>2015</risdate><volume>35</volume><issue>6</issue><spage>985</spage><epage>992</epage><pages>985-992</pages><issn>0271-678X</issn><eissn>1559-7016</eissn><abstract>Atrial fibrillation (AF) increases the risk and severity of thromboembolic stroke. Generally, antithrombotic agents increase the hemorrhagic risk of thromboembolic stroke. However, significant reductions in thromboembolism and intracerebral hemorrhage have been shown with the antithrombin dabigatran compared with warfarin. As thrombin has been implicated in microvessel injury during cerebral ischemia, we hypothesized that dabigatran decreases the risk of intracerebral hemorrhage by direct inhibition of the thrombin-mediated increase in cerebral endothelial cell permeability. Primary murine brain endothelial cells (mBECs) were exposed to murine thrombin before measuring permeability to 4-kDa fluorescein isothiocyanate-dextran. Thrombin increased mBEC permeability in a concentration-dependent manner, without significant endothelial cell death. Pretreatment of mBECs with dabigatran completely abrogated the effect of thrombin on permeability. Neither the expressions of the endothelial cell β1-integrins nor the tight junction protein claudin-5 were affected by thrombin exposure. Oxygen-glucose deprivation (OGD) also increased permeability; this effect was abrogated by treatment with dabigatran, as was the additive effect of thrombin and OGD on permeability. Taken together, these results indicate that dabigatran could contribute to a lower risk of intracerebral hemorrhage during embolism-associated ischemia from AF by protection of the microvessel permeability barrier from local thrombin challenge.</abstract><cop>London, England</cop><pub>SAGE Publications</pub><pmid>25669912</pmid><doi>10.1038/jcbfm.2015.9</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0271-678X |
| ispartof | Journal of cerebral blood flow and metabolism, 2015-06, Vol.35 (6), p.985-992 |
| issn | 0271-678X 1559-7016 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4640263 |
| source | Access via SAGE; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Animals Antithrombins - pharmacology Benzimidazoles - pharmacology beta-Alanine - analogs & derivatives beta-Alanine - pharmacology Brain - cytology Brain - drug effects Brain - metabolism Cell Survival - drug effects Cells, Cultured Claudin-5 - analysis Dabigatran Endothelial Cells - cytology Endothelial Cells - drug effects Endothelial Cells - metabolism Glucose - metabolism Integrin beta1 - analysis Male Mice Mice, Inbred C57BL Original Oxygen - metabolism Permeability - drug effects Thrombin - metabolism |
| title | Dabigatran Abrogates Brain Endothelial Cell Permeability in Response to Thrombin |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-15T21%3A08%3A13IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Dabigatran%20Abrogates%20Brain%20Endothelial%20Cell%20Permeability%20in%20Response%20to%20Thrombin&rft.jtitle=Journal%20of%20cerebral%20blood%20flow%20and%20metabolism&rft.au=Hawkins,%20Brian%20Thomas&rft.date=2015-06-01&rft.volume=35&rft.issue=6&rft.spage=985&rft.epage=992&rft.pages=985-992&rft.issn=0271-678X&rft.eissn=1559-7016&rft_id=info:doi/10.1038/jcbfm.2015.9&rft_dat=%3Cproquest_pubme%3E1684435685%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1683751636&rft_id=info:pmid/25669912&rft_sage_id=10.1038_jcbfm.2015.9&rfr_iscdi=true |