Hydroxychloroquine reverses the prothrombotic state in a mouse model of antiphospholipid syndrome: Role of reduced inflammation and endothelial dysfunction
Identifieur interne : 000017 ( France/Analysis ); précédent : 000016; suivant : 000018Hydroxychloroquine reverses the prothrombotic state in a mouse model of antiphospholipid syndrome: Role of reduced inflammation and endothelial dysfunction
Auteurs : Sébastien Miranda [France] ; Paul Billoir [France] ; Louise Damian [France] ; Pierre Alain Thiebaut [France] ; Damien Schapman [France] ; Maelle Le Besnerais [France] ; Fabienne Jouen [France] ; Ludovic Galas [France] ; Hervé Levesque [France] ; Véronique Le Cam-Duchez [France] ; Robinson Joannides [France] ; Vincent Richard [France] ; Ygal Benhamou [France]Source :
- PLoS ONE [ 1932-6203 ] ; 2019-03-14.
Abstract
Antiphospholipid antibodies (aPL) promote endothelial dysfunction, inflammation and pro-coagulant state. We investigated the effect of hydroxychloroquine (HCQ) on prothrombotic state and endothelial function in mice and in human aortic endothelial cells (HAEC). Human aPL were injected to C57BL/6 mice treated or not with HCQ. Vascular endothelial function and eNOS were assessed in isolated mesenteric arteries. Thrombosis was assessed both in vitro by measuring thrombin generation time (TGT) and tissue factor (TF) expression and in vivo by the measurement of the time to occlusion in carotid and the total thrombosis area in mesenteric arteries. TGT, TF, and VCAM1 expression were evaluated in HAEC. aPL increased VCAM-1 expression and reduced endothelium dependent relaxation to acetylcho-line. In parallel, aPL shortened the time to occlusion and extended thrombus area in mice. This was associated with an overexpression of TF and an increased TGT in mice and in HAEC. HCQ reduced clot formation as well as TGT, and improved endothelial-dependent relaxations. Finally, HCQ increased the p-eNOS/eNOS ratio. This study provides new evidence that HCQ improves procoagulant status and vascular function in APS by modulating eNOS, leading to an improvement in the production of NO.
Url:
DOI: 10.1371/journal.pone.0212614
Affiliations:
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Hal:inserm-02296602Le document en format XML
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CS 14032 - 14032 Caen Cedex 5</addrLine> <country key="FR"></country> </address> <ref type="url">http://www.normandie-univ.fr/</ref> </desc> </org></tutelle><tutelle active="#struct-300318" type="direct"><org type="institution" xml:id="struct-300318" status="VALID"> <idno type="ISNI">0000000121083034</idno> <idno type="IdRef">026403919</idno> <orgName>Université de Rouen Normandie</orgName> <orgName type="acronym">UNIROUEN</orgName> <date type="start">1966-01-01</date> <desc> <address> <addrLine>1, rue Thomas Becket 76821 Mont-Saint-Aignan Cedex</addrLine> <country key="FR"></country> </address> <ref type="url">http://www.univ-rouen.fr/</ref> </desc> <listRelation> <relation active="#struct-455934" type="direct"></relation> </listRelation> </org></tutelle></tutelles></hal:affiliation><country>France</country></affiliation></author><author><name sortKey="Le Cam Duchez, Veronique" sort="Le Cam Duchez, Veronique" uniqKey="Le Cam Duchez V" first="Véronique" last="Le Cam-Duchez">Véronique Le Cam-Duchez</name><affiliation wicri:level="1"><hal:affiliation type="laboratory" xml:id="struct-522489" status="VALID"> <idno type="RNSR">201220175G</idno> <orgName>Endothélium, valvulopathies et insuffisance cardiaque</orgName> <orgName type="acronym">EnVI</orgName> <date type="start">2017</date> <desc> <address> <addrLine>22 Boulevard Gambetta 76183 Rouen</addrLine> <country key="FR"></country> </address> <ref type="url">https://insermu1096.fr/</ref> </desc> <listRelation> <relation name="U1096" active="#struct-303623" type="direct"></relation> <relation name="U1096" active="#struct-300318" type="direct"></relation> <relation active="#struct-455934" type="indirect"></relation> </listRelation> <tutelles><tutelle name="U1096" active="#struct-303623" type="direct"><org type="institution" xml:id="struct-303623" status="VALID"> <idno type="IdRef">026388278</idno> <orgName>Institut National de la Santé et de la Recherche Médicale</orgName> <orgName type="acronym">INSERM</orgName> <desc> <address> <addrLine>101, rue de Tolbiac, 75013 Paris </addrLine> <country key="FR"></country> </address> <ref type="url">http://www.inserm.fr</ref> </desc> </org></tutelle><tutelle name="U1096" active="#struct-300318" type="direct"><org type="institution" xml:id="struct-300318" status="VALID"> <idno type="ISNI">0000000121083034</idno> <idno type="IdRef">026403919</idno> <orgName>Université de Rouen Normandie</orgName> <orgName type="acronym">UNIROUEN</orgName> <date type="start">1966-01-01</date> <desc> <address> <addrLine>1, rue Thomas Becket 76821 Mont-Saint-Aignan Cedex</addrLine> <country key="FR"></country> </address> <ref type="url">http://www.univ-rouen.fr/</ref> </desc> <listRelation> <relation active="#struct-455934" type="direct"></relation> </listRelation> </org></tutelle><tutelle active="#struct-455934" type="indirect"><org type="regroupinstitution" xml:id="struct-455934" status="VALID"> <idno type="IdRef">190906332</idno> <idno type="ISNI">0000000417859671 </idno> <orgName>Normandie Université</orgName> <orgName type="acronym">NU</orgName> <date type="start">2015-01-01</date> <desc> <address> <addrLine>Esplanade de la Paix - CS 14032 - 14032 Caen Cedex 5</addrLine> <country key="FR"></country> </address> <ref type="url">http://www.normandie-univ.fr/</ref> </desc> </org></tutelle></tutelles></hal:affiliation><country>France</country></affiliation></author><author><name sortKey="Joannides, Robinson" sort="Joannides, Robinson" uniqKey="Joannides R" first="Robinson" last="Joannides">Robinson Joannides</name><affiliation wicri:level="1"><hal:affiliation type="laboratory" xml:id="struct-522489" status="VALID"> <idno type="RNSR">201220175G</idno> <orgName>Endothélium, valvulopathies et insuffisance cardiaque</orgName> <orgName type="acronym">EnVI</orgName> <date type="start">2017</date> <desc> <address> <addrLine>22 Boulevard Gambetta 76183 Rouen</addrLine> <country key="FR"></country> </address> <ref type="url">https://insermu1096.fr/</ref> </desc> <listRelation> <relation name="U1096" active="#struct-303623" type="direct"></relation> <relation name="U1096" active="#struct-300318" type="direct"></relation> <relation active="#struct-455934" type="indirect"></relation> </listRelation> <tutelles><tutelle name="U1096" active="#struct-303623" type="direct"><org type="institution" xml:id="struct-303623" status="VALID"> <idno type="IdRef">026388278</idno> <orgName>Institut National de la Santé et de la Recherche Médicale</orgName> <orgName type="acronym">INSERM</orgName> <desc> <address> <addrLine>101, rue de Tolbiac, 75013 Paris </addrLine> <country key="FR"></country> </address> <ref type="url">http://www.inserm.fr</ref> </desc> </org></tutelle><tutelle name="U1096" active="#struct-300318" type="direct"><org type="institution" xml:id="struct-300318" status="VALID"> <idno type="ISNI">0000000121083034</idno> <idno type="IdRef">026403919</idno> <orgName>Université de Rouen Normandie</orgName> <orgName type="acronym">UNIROUEN</orgName> <date type="start">1966-01-01</date> <desc> <address> <addrLine>1, rue Thomas Becket 76821 Mont-Saint-Aignan Cedex</addrLine> <country key="FR"></country> </address> <ref type="url">http://www.univ-rouen.fr/</ref> </desc> <listRelation> <relation active="#struct-455934" type="direct"></relation> </listRelation> </org></tutelle><tutelle active="#struct-455934" type="indirect"><org type="regroupinstitution" xml:id="struct-455934" status="VALID"> <idno type="IdRef">190906332</idno> <idno type="ISNI">0000000417859671 </idno> <orgName>Normandie Université</orgName> <orgName type="acronym">NU</orgName> <date type="start">2015-01-01</date> <desc> <address> <addrLine>Esplanade de la Paix - CS 14032 - 14032 Caen Cedex 5</addrLine> <country key="FR"></country> </address> <ref type="url">http://www.normandie-univ.fr/</ref> </desc> </org></tutelle></tutelles></hal:affiliation><country>France</country></affiliation></author><author><name sortKey="Richard, Vincent" sort="Richard, Vincent" uniqKey="Richard V" first="Vincent" last="Richard">Vincent Richard</name><affiliation wicri:level="1"><hal:affiliation type="laboratory" xml:id="struct-522489" status="VALID"> <idno type="RNSR">201220175G</idno> <orgName>Endothélium, valvulopathies et insuffisance cardiaque</orgName> <orgName type="acronym">EnVI</orgName> <date type="start">2017</date> <desc> <address> <addrLine>22 Boulevard Gambetta 76183 Rouen</addrLine> <country key="FR"></country> </address> <ref type="url">https://insermu1096.fr/</ref> </desc> <listRelation> <relation name="U1096" active="#struct-303623" type="direct"></relation> <relation name="U1096" active="#struct-300318" type="direct"></relation> <relation active="#struct-455934" type="indirect"></relation> </listRelation> <tutelles><tutelle name="U1096" active="#struct-303623" type="direct"><org type="institution" xml:id="struct-303623" status="VALID"> <idno type="IdRef">026388278</idno> <orgName>Institut National de la Santé et de la Recherche Médicale</orgName> <orgName type="acronym">INSERM</orgName> <desc> <address> <addrLine>101, rue de Tolbiac, 75013 Paris </addrLine> <country key="FR"></country> </address> <ref type="url">http://www.inserm.fr</ref> </desc> </org></tutelle><tutelle name="U1096" active="#struct-300318" type="direct"><org type="institution" xml:id="struct-300318" status="VALID"> <idno type="ISNI">0000000121083034</idno> <idno type="IdRef">026403919</idno> <orgName>Université de Rouen Normandie</orgName> <orgName type="acronym">UNIROUEN</orgName> <date type="start">1966-01-01</date> <desc> <address> <addrLine>1, rue Thomas Becket 76821 Mont-Saint-Aignan Cedex</addrLine> <country key="FR"></country> </address> <ref type="url">http://www.univ-rouen.fr/</ref> </desc> <listRelation> <relation active="#struct-455934" type="direct"></relation> </listRelation> </org></tutelle><tutelle active="#struct-455934" type="indirect"><org type="regroupinstitution" xml:id="struct-455934" status="VALID"> <idno type="IdRef">190906332</idno> <idno type="ISNI">0000000417859671 </idno> <orgName>Normandie Université</orgName> <orgName type="acronym">NU</orgName> <date type="start">2015-01-01</date> <desc> <address> <addrLine>Esplanade de la Paix - CS 14032 - 14032 Caen Cedex 5</addrLine> <country key="FR"></country> </address> <ref type="url">http://www.normandie-univ.fr/</ref> </desc> </org></tutelle></tutelles></hal:affiliation><country>France</country></affiliation></author><author><name sortKey="Benhamou, Ygal" sort="Benhamou, Ygal" uniqKey="Benhamou Y" first="Ygal" last="Benhamou">Ygal Benhamou</name><affiliation wicri:level="1"><hal:affiliation type="laboratory" xml:id="struct-18150" status="VALID"> <orgName>Service de Médecine Interne [Rouen]</orgName> <desc> <address> <addrLine>CHU de Rouen1 rue de Germont, 76031 Rouen cedex</addrLine> <country key="FR"></country> </address> </desc> <listRelation> <relation active="#struct-300147" type="direct"></relation> <relation active="#struct-455934" type="indirect"></relation> <relation active="#struct-300318" type="direct"></relation> </listRelation> <tutelles><tutelle active="#struct-300147" type="direct"><org type="institution" xml:id="struct-300147" status="VALID"> <idno type="IdRef">169975681</idno> <orgName>CHU Rouen</orgName> <desc> <address> <addrLine>1, rue de Germont 76031 Rouen cedex</addrLine> <country key="FR"></country> </address> <ref type="url">https://www.chu-rouen.fr/</ref> </desc> <listRelation> <relation active="#struct-455934" type="direct"></relation> </listRelation> </org></tutelle><tutelle active="#struct-455934" type="indirect"><org type="regroupinstitution" xml:id="struct-455934" status="VALID"> <idno type="IdRef">190906332</idno> <idno type="ISNI">0000000417859671 </idno> <orgName>Normandie Université</orgName> <orgName type="acronym">NU</orgName> <date type="start">2015-01-01</date> <desc> <address> <addrLine>Esplanade de la Paix - CS 14032 - 14032 Caen Cedex 5</addrLine> <country key="FR"></country> </address> <ref type="url">http://www.normandie-univ.fr/</ref> </desc> </org></tutelle><tutelle active="#struct-300318" type="direct"><org type="institution" xml:id="struct-300318" status="VALID"> <idno type="ISNI">0000000121083034</idno> <idno type="IdRef">026403919</idno> <orgName>Université de Rouen Normandie</orgName> <orgName type="acronym">UNIROUEN</orgName> <date type="start">1966-01-01</date> <desc> <address> <addrLine>1, rue Thomas Becket 76821 Mont-Saint-Aignan Cedex</addrLine> <country key="FR"></country> </address> <ref type="url">http://www.univ-rouen.fr/</ref> </desc> <listRelation> <relation active="#struct-455934" type="direct"></relation> </listRelation> </org></tutelle></tutelles></hal:affiliation><country>France</country></affiliation></author></analytic><idno type="DOI">10.1371/journal.pone.0212614</idno><series><title level="j">PLoS ONE</title><idno type="ISSN">1932-6203</idno><imprint><date type="datePub">2019-03-14</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"> <p>Antiphospholipid antibodies (aPL) promote endothelial dysfunction, inflammation and pro-coagulant state. We investigated the effect of hydroxychloroquine (HCQ) on prothrombotic state and endothelial function in mice and in human aortic endothelial cells (HAEC). Human aPL were injected to C57BL/6 mice treated or not with HCQ. Vascular endothelial function and eNOS were assessed in isolated mesenteric arteries. Thrombosis was assessed both in vitro by measuring thrombin generation time (TGT) and tissue factor (TF) expression and in vivo by the measurement of the time to occlusion in carotid and the total thrombosis area in mesenteric arteries. TGT, TF, and VCAM1 expression were evaluated in HAEC. aPL increased VCAM-1 expression and reduced endothelium dependent relaxation to acetylcho-line. In parallel, aPL shortened the time to occlusion and extended thrombus area in mice. This was associated with an overexpression of TF and an increased TGT in mice and in HAEC. HCQ reduced clot formation as well as TGT, and improved endothelial-dependent relaxations. Finally, HCQ increased the p-eNOS/eNOS ratio. This study provides new evidence that HCQ improves procoagulant status and vascular function in APS by modulating eNOS, leading to an improvement in the production of NO.</p> </div></front></TEI><affiliations><list><country><li>France</li></country></list><tree><country name="France"><noRegion><name sortKey="Miranda, Sebastien" sort="Miranda, Sebastien" uniqKey="Miranda S" first="Sébastien" last="Miranda">Sébastien Miranda</name></noRegion><name sortKey="Benhamou, Ygal" sort="Benhamou, Ygal" uniqKey="Benhamou Y" first="Ygal" last="Benhamou">Ygal Benhamou</name><name sortKey="Billoir, Paul" sort="Billoir, Paul" uniqKey="Billoir P" first="Paul" last="Billoir">Paul Billoir</name><name sortKey="Damian, Louise" sort="Damian, Louise" uniqKey="Damian L" first="Louise" last="Damian">Louise Damian</name><name sortKey="Galas, Ludovic" sort="Galas, Ludovic" uniqKey="Galas L" first="Ludovic" last="Galas">Ludovic Galas</name><name sortKey="Joannides, Robinson" sort="Joannides, Robinson" uniqKey="Joannides R" first="Robinson" last="Joannides">Robinson Joannides</name><name sortKey="Jouen, Fabienne" sort="Jouen, Fabienne" uniqKey="Jouen F" first="Fabienne" last="Jouen">Fabienne Jouen</name><name sortKey="Le Besnerais, Maelle" sort="Le Besnerais, Maelle" uniqKey="Le Besnerais M" first="Maelle" last="Le Besnerais">Maelle Le Besnerais</name><name sortKey="Le Cam Duchez, Veronique" sort="Le Cam Duchez, Veronique" uniqKey="Le Cam Duchez V" first="Véronique" last="Le Cam-Duchez">Véronique Le Cam-Duchez</name><name sortKey="Levesque, Herve" sort="Levesque, Herve" uniqKey="Levesque H" first="Hervé" last="Levesque">Hervé Levesque</name><name sortKey="Richard, Vincent" sort="Richard, Vincent" uniqKey="Richard V" first="Vincent" last="Richard">Vincent Richard</name><name sortKey="Schapman, Damien" sort="Schapman, Damien" uniqKey="Schapman D" first="Damien" last="Schapman">Damien Schapman</name><name sortKey="Thiebaut, Pierre Alain" sort="Thiebaut, Pierre Alain" uniqKey="Thiebaut P" first="Pierre Alain" last="Thiebaut">Pierre Alain Thiebaut</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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