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Background Anticoagulants induce atherosclerosis regression in animal models but exploiting this clinically is limited by bleeding events. Here we test a novel thrombin inhibitor, PTL060, comprising hirulog covalently linked to a synthetic myristoyl electrostatic switch to tether to cell membranes. Methods and Results ApoE-/- mice were fed chow or high-fat diets, before transplantation of congenic aortic segments or injection of PTL060, parental hirulog, control saline, or labeled CD11b positive cells. Aortic transplants from transgenic mice expressing anticoagulants on endothelium did not develop atherosclerosis. A single intravenous injection of PTL060, but not hirulog inhibited atheroma development by >50% compared with controls when assessed 4 weeks later. Mice had prolonged bleeding times for only one seventh of the time that PTL060 was biologically active. Repeated weekly injections of PTL060 but not hirulog caused regression of atheroma. We dissected 2 contributory mechanisms. First, the majority of CCR2+ (C-C chemokine receptor type 2+) monocytes recruited into plaques expressed CCR7 (C-C chemokine receptor type 7), ABCA1 (ATP-binding cassette transporter - 1), and interleukin-10 in PTL060 mice, a phenotype seen in <20% of CCR2+ recruits in controls. Second, after several doses, there was a significant reduction in monocyte recruits, the majority of which were CCR2-negative with a similar regression-associated phenotype. Regression equivalent to that induced by intravenous PTL060 was induced by adoptive transfer of CD11b+ cells pre-coated with PTL060. Conclusions Covalent linkage of a myristoyl electrostatic switch onto hirulog in PTL060 uncouples the pharmacodynamic effects on hemostasis and atherosclerosis, such that plaque regression, mediated predominantly via effects on monocytes, is accompanied by only transient anticoagulation.

背景

抗凝剂可在动物模型中诱导动脉粥样硬化消退，但由于出血事件的限制，在临床上利用这一作用受到限制。在此，我们测试了一种新型凝血酶抑制剂 PTL060，它由与合成豆蔻酰静电开关共价连接的 hirulog 组成，以与细胞膜结合。

方法和结果

apoE-/-小鼠先喂食普通饲料或高脂肪饲料，然后移植同源主动脉段或注射 PTL060、亲本 hirulog、对照生理盐水或标记的 CD11b 阳性细胞。在表达抗凝剂的转基因小鼠中，主动脉移植不会发生动脉粥样硬化。与对照组相比，在 4 周后评估时，单次静脉注射 PTL060 而非 hirulog 可使动脉粥样硬化发展减少 50%以上。与 PTL060 的生物学活性持续时间相比，小鼠的出血时间仅延长了七分之一。每周重复注射 PTL060 而非 hirulog 可导致动脉粥样硬化消退。我们剖析了 2 种促成机制。首先，在 PTL060 小鼠中，大多数募集到斑块中的 CCR2+（C-趋化因子受体类型 2+）单核细胞表达 CCR7（C-趋化因子受体类型 7）、ABCA1（ATP 结合盒转运体-1）和白细胞介素-10，在对照组中，<20%的 CCR2+募集细胞具有这种表型。其次，经过几次剂量后，单核细胞募集数量显著减少，其中大多数是 CCR2-阴性，具有类似的消退相关表型。通过预先用 PTL060 包被的 CD11b+细胞的过继转移，可诱导与静脉内 PTL060 诱导的消退等效的消退。