Abstract
BackgroundAntiphospholipid syndrome is associated with endothelial dysfunction, which leads to thrombosis and early atheroma. Given that hydroxychloroquine has anti-thrombotic properties in lupus, we hypothesized that it could reduce endothelial dysfunction in an animal model of antiphospholipid syndrome. We evaluated the effect of hydroxychloroquine in preventing endothelial dysfunction in a mouse model of antiphospholipid syndrome.MethodsAntiphospholipid syndrome was induced by an injection of monoclonal anti-beta-2-GPI antibodies. Vascular reactivity was evaluated in mesenteric resistance arteries isolated from mice 3 weeks (APL3W) after receiving a single injection of anti-beta-2-GPI antibodies and after 3 weeks of daily oral hydroxychloroquine treatment (HCQ3W) compared to control mice (CT3W). We evaluated endothelial dysfunction by measuring acetylcholine-mediated vasodilation. A pharmacological approach was used to evaluate NO synthase uncoupling (tetrahydrobiopterin) and the generation of reactive oxygen species (Tempol).ResultsImpaired acetylcholine-mediated dilation was evidenced in mice 3 weeks after anti-beta-2-GPI antibodies injection compared to CT3W, by reduced maximal dilation (p<0.0001) and sensitivity (pKd) (p = 0.01) to acetylcholine. Hydroxychloroquine improved acetylcholine-dependent dilation, on pKd (p = 0.02) but not maximal capacity compared to untreated mice. The addition of tetrahydrobiopterin (p = 0.02) and/or Tempol (p = 0.0008) improved acetylcholine-mediated dilation in APL3W but not in HCQ3W.ConclusionsWe demonstrated that endothelial dysfunction in mouse resistance arteries persisted at 3 weeks after a single injection of monoclonal anti-beta-2-GPI antibodies, and that hydroxychloroquine improved endothelium-dependent dilation at 3 weeks, through improvement of NO synthase coupling and oxidative stress reduction.
Highlights
The current classification criteria of antiphospholipid syndrome (APS) requires at least one clinical manifestation, thrombosis or pregnancy morbidity, in the presence of at least one serological assay, anticardiolipin antibodies, anti-beta-2-GPI antibodies and lupus anticoagulant, on 2 occasions 12 weeks apart [1].Beta-2-GPI (B2GPI) seems to be the most relevant target of antiphospholipid antibodies [2]
Antiphospholipid syndrome is associated with endothelial dysfunction, which leads to thrombosis and early atheroma
We evaluated the effect of hydroxychloroquine in preventing endothelial dysfunction in a mouse model of antiphospholipid syndrome
Summary
Beta-2-GPI (B2GPI) seems to be the most relevant target of antiphospholipid antibodies (aPL) [2]. The binding of antibodies against B2GPI has been shown to activate EC in mouse models of APS [7] and APS patients, inducing a proinflammatory and procoagulant phenotype in EC via up-regulation of adhesion molecules and cytokines, known as endothelial dysfunction (ED) [8]. Ramesh et al have shown that antiphospholipid antibodies (aPL) inhibit endothelial NO synthase (eNOS), with the reduced NO production causing leukocyte–EC interaction and thrombus formation. Antiphospholipid syndrome is associated with endothelial dysfunction, which leads to thrombosis and early atheroma. Given that hydroxychloroquine has anti-thrombotic properties in lupus, we hypothesized that it could reduce endothelial dysfunction in an animal model of antiphospholipid syndrome. We evaluated the effect of hydroxychloroquine in preventing endothelial dysfunction in a mouse model of antiphospholipid syndrome
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