Systems Immunity Research Institute, School of Medicine, Cardiff University, CF14 4XN Cardiff, United Kingdom.
Division of Infection and Immunity, School of Medicine, Cardiff University, CF14 4XN Cardiff, United Kingdom.
Proc Natl Acad Sci U S A. 2019 Apr 16;116(16):8038-8047. doi: 10.1073/pnas.1814409116. Epub 2019 Apr 3.
Abdominal aortic aneurysm (AAA) is an inflammatory vascular disease with high mortality and limited treatment options. How blood lipids regulate AAA development is unknown. Here lipidomics and genetic models demonstrate a central role for procoagulant enzymatically oxidized phospholipids (eoxPL) in regulating AAA. Specifically, through activating coagulation, eoxPL either promoted or inhibited AAA depending on tissue localization. Ang II administration to mice increased intravascular coagulation during AAA development. Lipidomics revealed large numbers of eoxPL formed within mouse and human AAA lesions. Deletion of eoxPL-generating enzymes ( or ) or administration of the factor Xa inhibitor rivaroxaban significantly reduced AAA. -deficient mice displayed constitutively dysregulated hemostasis, including a consumptive coagulopathy, characterized by compensatory increase in prothrombotic aminophospholipids (aPL) in circulating cell membranes. Intravenously administered procoagulant PL caused clotting factor activation and depletion, induced a bleeding defect, and significantly reduced AAA development. These data suggest that deletion reduces AAA through diverting coagulation away from the vessel wall due to eoxPL deficiency, instead activating clotting factor consumption and depletion in the circulation. In mouse whole blood, ∼44 eoxPL molecular species formed within minutes of clot initiation. These were significantly elevated with deletion, and many were absent in mice, identifying specific eoxPL that modulate AAA. Correlation networks demonstrated eoxPL belonged to subfamilies defined by oxylipin composition. Thus, procoagulant PL regulate AAA development through complex interactions with clotting factors. Modulation of the delicate balance between bleeding and thrombosis within either the vessel wall or circulation was revealed that can either drive or prevent disease development.
腹主动脉瘤（AAA）是一种炎症性血管疾病，死亡率高，治疗选择有限。血液脂质如何调节 AAA 的发展尚不清楚。脂质组学和遗传模型表明，促凝血酶促氧化磷脂（eoxPL）在调节 AAA 中起核心作用。具体而言，通过激活凝血，eoxPL 根据组织定位促进或抑制 AAA。血管紧张素 II 给药可在 AAA 发展过程中增加血管内凝血。脂质组学揭示了大量的 eoxPL 在小鼠和人类 AAA 病变中形成。eoxPL 生成酶（或）的缺失或因子 Xa 抑制剂利伐沙班的给药显著减少了 AAA。缺乏的小鼠表现出持续失调的止血，包括消耗性凝血病，其特征是循环细胞膜中促血栓性氨基磷脂（aPL）的代偿性增加。静脉内给予促凝血 PL 会引起凝血因子激活和耗竭，导致出血缺陷，并显著减少 AAA 的发展。这些数据表明，由于 eoxPL 缺乏，缺失减少了 AAA，而是由于血管壁上的 eoxPL 缺乏，转而激活循环中的凝血因子消耗和耗竭。在小鼠全血中，在凝血起始后几分钟内形成了约 44 种 eoxPL 分子物种。这些在缺失时显著升高，并且在缺失的小鼠中许多不存在，确定了调节 AAA 的特定 eoxPL。相关网络表明，eoxPL 属于由氧代脂质组成定义的亚家族。因此，促凝血 PL 通过与凝血因子的复杂相互作用调节 AAA 的发展。在血管壁或循环内的出血和血栓形成之间的微妙平衡的调节被揭示出来，这可以驱动或预防疾病的发展。
