UMR CNRS 6015-INSERM U1083, MITOVASC Institute, Université d'Angers, Faculté de Médecine, Bâtiment IRIS 2, Angers, France.
Service de Médecine Interne et Maladies Vasculaires, Centre Hospitalier Universitaire, Angers, France.
PLoS One. 2018 Nov 6;13(11):e0206814. doi: 10.1371/journal.pone.0206814. eCollection 2018.
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.
Antiphospholipid 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).
Impaired 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.
We 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.
抗磷脂综合征与内皮功能障碍有关，导致血栓形成和早期动脉粥样硬化。鉴于羟氯喹在狼疮中有抗血栓作用，我们假设它可以在抗磷脂综合征的动物模型中减少内皮功能障碍。我们评估了羟氯喹在预防抗磷脂综合征小鼠模型内皮功能障碍中的作用。
通过注射单克隆抗β-2-GPI 抗体诱导抗磷脂综合征。在接受单次抗β-2-GPI 抗体注射后 3 周（APL3W）和接受 3 周每日口服羟氯喹治疗（HCQ3W）后，评估从小鼠肠系膜阻力动脉分离的血管反应性，并与对照小鼠（CT3W）进行比较。我们通过测量乙酰胆碱介导的血管舒张来评估内皮功能障碍。使用药理学方法评估一氧化氮合酶解偶联（四氢生物蝶呤）和活性氧的产生（Tempol）。
与 CT3W 相比，在接受抗β-2-GPI 抗体注射后 3 周，小鼠的乙酰胆碱介导的舒张受损，表现为最大舒张（p<0.0001）和乙酰胆碱敏感性（pKd）（p = 0.01）降低。与未治疗的小鼠相比，羟氯喹改善了乙酰胆碱依赖性舒张，表现在 pKd （p = 0.02），但不是最大能力。在 APL3W 中添加四氢生物蝶呤（p = 0.02）和/或 Tempol（p = 0.0008）改善了乙酰胆碱介导的舒张，但在 HCQ3W 中没有改善。
我们证明了在单次注射单克隆抗β-2-GPI 抗体后 3 周，小鼠阻力动脉中的内皮功能障碍持续存在，羟氯喹通过改善一氧化氮合酶偶联和减少氧化应激来改善 3 周时的内皮依赖性舒张。
