Hydroxychloroquine reverses the prothrombotic state in a mouse model of antiphospholipid syndrome: Role of reduced inflammation and endothelial dysfunction

Sébastien Miranda; Paul Billoir; Louise Damian; Pierre Thiebaut; Damien Schapman; Maelle Le Besnerais; Fabienne Jouen; Ludovic Galas; Hervé Levesque; Véronique Le Cam-Duchez; Robinson Joannides; Vincent Richard; Ygal Benhamou

Hydroxychloroquine reverses the prothrombotic state in a mouse model of antiphospholipid syndrome: Role of reduced inflammation and endothelial dysfunction

Sébastien Miranda ^{1, 2, 3} Paul Billoir ^{2, 4} Louise Damian ^{1, 2, 3} Pierre Thiebaut ^{1, 2, 3} Damien Schapman ^{3, 5} Maelle Le Besnerais ^{1, 2, 3} Fabienne Jouen ^{3, 6} Ludovic Galas ^{3, 5} Hervé Levesque ^{1, 2, 3} Véronique Le Cam-Duchez ^{2, 4} Robinson Joannides ^{2, 3} Vincent Richard ^{2, 3} Ygal Benhamou ^{1, 2, 3, *}

* Corresponding author

1 Service de Médecine Interne [Rouen]

2 EnVI - Endothélium, valvulopathies et insuffisance cardiaque

3 IRIB - Institute for Research and Innovation in Biomedicine

4 Laboratoire d'hématologie [Rouen]

5 PRIMACEN - Plate-Forme de Recherche en Imagerie Cellulaire de Haute-Normandie

6 PANTHER - Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices

Abstract : Antiphospholipid antibodies (aPL) promote endothelial dysfunction, inflammation and procoagulant 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 acetylcholine. 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.

Document type :

Journal articles

Domain :

Life Sciences [q-bio] / Human health and pathology / Cardiology and cardiovascular system

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https://www.hal.inserm.fr/inserm-02262294
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Submitted on : Friday, August 2, 2019 - 11:28:05 AM
Last modification on : Monday, September 2, 2019 - 10:56:01 AM

journal.pone.0212614.pdf

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Hydroxychloroquine reverses the prothrombotic state in a mouse model of antiphospholipid syndrome: Role of reduced inflammation and endothelial dysfunction

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Hydroxychloroquine reverses the prothrombotic state in a mouse model of antiphospholipid syndrome: Role of reduced inflammation and endothelial dysfunction

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