Neutrophil-derived myeloperoxidase promotes atherogenesis and neointima formation in mice
Neutrophil-derived myeloperoxidase promotes atherogenesis and neointima formation in mice
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DOI：
10.1016/j.ijcard.2015.11.128
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发表时间：
2016-02-01
影响因子：
3.5
通讯作者：
Andrie, Rene P.
中科院分区：
文献类型：
--
作者：
Tiyerili, Vedat;Camara, Bakary;Andrie, Rene P.
背景：髓过氧化物酶（MPO）主要表达于中性粒细胞，是一种与炎症和氧化应激相关的酶。MPO是健康个体和冠状动脉疾病患者的独立预后标志物。在本研究中，我们分析了MPO在实验性动脉粥样硬化形成和血管injury in mice.Methods和results后的新生内膜形成中的作用：6-8周龄载脂蛋白E缺陷（ApoE（-/-））小鼠8周喂养高胆固醇饮食，伴随治疗两种不同剂量（10 μ g/mg bw vs. 20 μ g/mg bw）的4-ABAH（MPO抑制剂）。低剂量应用不影响氧化应激、内皮功能和动脉粥样硬化斑块的发展。4-高剂量ABAH可降低炎症标志物和血管氧化应激，持续改善内皮功能，显著减少动脉粥样硬化斑块的形成。为了评估循环细胞内MPO的作用，用来自MPO（-/-）小鼠的骨髓衍生细胞重新填充经辐射的ApoE（-/-）小鼠，并喂食高胆固醇饮食8周。这种MPO缺乏导致炎症减轻，氧化应激降低，内皮功能改善，对斑块形成有显著影响。为了了解MPO在血管重塑中的可能作用，我们检测了其对小鼠血管损伤后新生内膜形成的影响。4-ABAH抑制MPO可明显减少新生内膜的形成。它显着减少MPO缺陷小鼠，而从WT小鼠脾源性中性粒细胞的转移增强它。结论：我们的数据表明，MPO在动脉粥样硬化形成的发病机制中的核心作用，更喜欢药理MPO抑制作为预防和治疗动脉粥样硬化和再狭窄的治疗策略。(C)2015爱思唯尔爱尔兰有限公司版权所有。
Background: Myeloperoxidase (MPO), expressed mainly in neutrophils, is an enzyme linked to inflammation and oxidative stress. MPO is an independent prognostic marker in healthy individuals as well as in patients with coronary artery disease. In this present study we analyze the role of MPO in experimental atherogenesis and neointima formation after vascular injury in mice.Methods and results: 6-8 weeks old apolipoprotein E-deficient (ApoE(-/-)) mice were fed a high-cholesterol diet for 8 weeks with concomitant treatment with two different doses (10 mu g/mg bw vs. 20 mu g/mg bw) of 4-ABAH (MPO inhibitor). Application at lower dosage did not affect oxidative stress, endothelial function and atherosclerotic plaque development. 4-ABAH in higher dosage decreased inflammatory markers and vascular oxidative stress, consecutively improved endothelial function and reduced significantly atherosclerotic plaque development. To assess the role of circulating intracellular MPO, irradiated ApoE(-/-) mice were repopulated with bone marrow-derived cells from MPO(-/-)mice and were fed a high-cholesterol diet for 8 weeks. This MPO deficiency resulted in alleviated inflammation, reduced oxidative stress and improved endothelial function with a significant impact on plaque formation. To understand the possible role of MPO in vascular remodeling, we tested its effects on neointima formation following vascular injury in mice. MPO inhibition by 4-ABAH reduced significantly neointima formation. It was significantly reduced in MPO deficient mice, whereas transfer of spleen-derived neutrophils from WT mice enhanced it.Conclusion: Our data suggests a central role of MPO in the pathogenesis of atherogenesis and prefers pharmacological MPO inhibition as a therapeutic strategy for prevention and therapy of atherosclerosis and restenosis. (C) 2015 Elsevier Ireland Ltd. All rights reserved.