Institute for Pharmacology and Clinical Pharmacology, Medical Faculty, University Hospital, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany; Cardiovascular Research Institute Duesseldorf (CARID), University Hospital, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.
Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center at the Heinrich-Heine-University Duesseldorf, Leibniz Center for Diabetes Research, Duesseldorf, Germany; German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany.
Atherosclerosis. 2019 Aug;287:81-88. doi: 10.1016/j.atherosclerosis.2019.06.897. Epub 2019 Jun 8.
The non-vitamin K oral anticoagulant dabigatran etexilate (dabigatran) is increasingly prescribed to patients with non-valvular atrial fibrillation and venous thromboembolism. Adipose tissue (AT) inflammation during obesity plays a crucial role in the development of insulin resistance, type II diabetes and atherogenesis. The aim of the present study was to investigate the effects of thrombin inhibition by dabigatran in a combined model of diet-induced obesity and atherosclerosis.
Female Low density lipoprotein receptor knockout (Lldr) mice were fed a high-fat diet containing 5 mg/g dabigatran or matching control for 20 weeks.
Dabigatran-treated animals showed increased adipocyte hypertrophy, but reduced numbers of pro-inflammatory M1-polarized macrophages in the adipose tissue. Abundance of pro-inflammatory M1 macrophages was also decreased in the aortic wall of dabigatran-fed mice. Multiple circulating cytokines were reduced, indicating an effect in systemically relevant secretory compartments such as the AT.
Dabigatran treatment reduces pro-inflammatory M1 macrophages in atherosclerotic lesions, thereby contributing to plaque stabilizing and atheroprotective effects of the thrombin inhibitor. This finding is not restricted to the vascular wall but is also present in AT where dabigatran treatment reduced the release of pro-inflammatory cytokines and accumulation of M1 macrophages.
非维生素 K 口服抗凝剂达比加群酯（达比加群）越来越多地被用于治疗非瓣膜性心房颤动和静脉血栓栓塞症患者。肥胖时脂肪组织（AT）炎症在胰岛素抵抗、2 型糖尿病和动脉粥样硬化的发生发展中起着关键作用。本研究旨在研究凝血酶抑制对饮食诱导肥胖和动脉粥样硬化合并模型的影响。
雌性低密度脂蛋白受体敲除（Lldr）小鼠喂食含有 5mg/g 达比加群或匹配对照的高脂肪饮食 20 周。
达比加群治疗的动物表现出脂肪细胞肥大增加，但脂肪组织中促炎 M1 极化巨噬细胞数量减少。给予达比加群的小鼠主动脉壁中促炎 M1 巨噬细胞的丰度也降低。多种循环细胞因子减少，表明在 AT 等全身相关分泌隔室中存在作用。
达比加群治疗可减少动脉粥样硬化病变中的促炎 M1 巨噬细胞，从而有助于稳定斑块和发挥凝血酶抑制剂的抗动脉粥样硬化作用。这一发现不仅限于血管壁，在 AT 中也存在，达比加群治疗减少了促炎细胞因子的释放和 M1 巨噬细胞的积累。
