Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany.
J Am Coll Cardiol. 2010 Nov 23;56(22):1847-57. doi: 10.1016/j.jacc.2010.04.066.
A nonagonist monocyte chemotactic protein-1 (MCP-1/CCL2) mutant (PA508) with increased affinity for glycosaminoglycans and thus competing with CCL2 was evaluated as a candidate for preventing neointima formation or myocardial ischemia/reperfusion injury.
Myocardial infarction (MI) remains a major cause of death worldwide despite improved interventional and therapeutic options. Therefore, the discovery of drugs that limit restenosis after intervention and post-MI damage remains an important challenge.
The function of PA508 was assessed in functional assays in vitro and in mouse models of wire-induced neointima formation and experimental MI.
PA508 was functionally inactive in CC chemokine receptor 2 (CCR2) binding and calcium influx but inhibited monocyte chemotaxis or transendothelial migration toward CCL2, suggesting that it interferes with CCL2 presentation. In wild-type but not CCR2-deficient mice, PA508 reduced inflammatory leukocyte recruitment without affecting differential leukocyte counts, CCL2 levels, organ function, or morphology, indicating that it specifically attenuates the CCL2-CCR2 axis. Compared with vehicle, daily intraperitoneal injection of PA508 significantly (p < 0.05, n = 5) reduced neointimal plaque area and mononuclear cell infiltration in carotid arteries of hyperlipidemic apolipoprotein E-deficient mice while increasing smooth muscle cell content. In C57Bl/6J mice that underwent myocardial ischemia/reperfusion, treatment with PA508 significantly reduced infarction size, monocyte infiltration, and collagen and myofibroblast content in the infarction area and preserved heart function compared with vehicle (p < 0.05, n = 4 to 8).
Here we demonstrate that administration of a rationally designed CCL2 competitor reduced inflammatory monocyte recruitment, limited neointimal hyperplasia, and attenuated myocardial ischemia/reperfusion injury in mice and could therefore be envisioned as a combined therapeutic approach for restenosis and MI.
一种对糖胺聚糖具有更高亲和力的非九聚体单核细胞趋化蛋白-1（MCP-1/CCL2）突变体（PA508）被评估为预防内膜增生或心肌缺血/再灌注损伤的候选药物，因其与 CCL2 竞争。
尽管介入和治疗选择有所改善，但心肌梗死（MI）仍然是全球范围内主要的死亡原因。因此，发现可限制介入后再狭窄和 MI 后损伤的药物仍然是一个重要挑战。
在体外功能测定和导线诱导的内膜增生和实验性 MI 小鼠模型中评估 PA508 的功能。
PA508 在 CC 趋化因子受体 2（CCR2）结合和钙内流方面无功能活性，但抑制单核细胞趋化或向 CCL2 的跨内皮迁移，表明其干扰 CCL2 的呈现。在野生型但不是 CCR2 缺陷型小鼠中，PA508 减少炎症性白细胞募集而不影响白细胞分类计数、CCL2 水平、器官功能或形态，表明其特异性减弱 CCL2-CCR2 轴。与载体相比，每天腹腔注射 PA508 可显著（p < 0.05，n = 5）降低高脂血症载脂蛋白 E 缺陷型小鼠颈动脉中的新生内膜斑块面积和单核细胞浸润，同时增加平滑肌细胞含量。在接受心肌缺血/再灌注的 C57Bl/6J 小鼠中，与载体相比，PA508 治疗可显著减少梗死面积、单核细胞浸润以及梗死区的胶原和肌成纤维细胞含量，并保留心脏功能（p < 0.05，n = 4 至 8）。
在这里，我们证明了一种合理设计的 CCL2 竞争物的给药可减少炎症性单核细胞募集，限制内膜增生，并减轻小鼠的心肌缺血/再灌注损伤，因此可以想象为治疗再狭窄和 MI 的联合治疗方法。
