The CXCR4 antagonist POL5551 is equally effective as sirolimus in reducing neointima formation without impairing re-endothelialisation
The CXCR4 antagonist POL5551 is equally effective as sirolimus in reducing neointima formation without impairing re-endothelialisation
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DOI：
10.1160/th11-07-0453
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发表时间：
2012-02-01
影响因子：
6.7
通讯作者：
Schober, Andreas
中科院分区：
文献类型：
--
作者：
Hamesch, Karim;Subramanian, Pallavi;Schober, Andreas
药物洗脱支架植入后内皮恢复受损是一个主要问题，因为它增加了晚期支架血栓形成的风险。趋化因子轴CXCL12/CXCR4的破坏通过阻断平滑肌祖细胞的募集来抑制新内膜的形成。为了直接比较以CXCR4为靶点的治疗策略与目前用于支架涂层的药物，我们研究了CXCR4拮抗剂POL5551和西罗莫司对新内膜形成的影响。载脂蛋白e缺陷小鼠在颈动脉导线损伤后连续用POL5551或西罗莫司治疗28天。POL5551对新生内膜形成的抑制作用为63%（剂量为2mg /kg/天）和70%（剂量为20mg /kg/天）。相比之下，西罗莫司减少了69%的内膜面积。与损伤后前三天用POL5551治疗相比，每天注射一次POL5551 (20 mg/kg)，连续28天，新生内膜增生减少53%。对新内膜细胞组成的分析显示，用高剂量POL5551治疗的小鼠的相对平滑肌细胞（SMC）和巨噬细胞含量减少。相反，西罗莫司治疗后SMC含量的降低与巨噬细胞的新内膜富集有关。此外，西罗莫司损害内皮细胞的恢复，而POL5551没有。因此，POL5551对CXCR4的抑制在预防新内膜形成方面与西罗莫司同样有效，但POL5551可能更有益，因为用它治疗会导致更稳定的病变表型，而且不会损害再内皮化。
Impaired endothelial recovery after the implantation of drug-eluting stents is a major concern because of the increased risk for late stent thrombosis. The disruption of the chemokine axis CXCL12/CXCR4 inhibits neointima formation by blocking the recruitment of smooth muscle progenitor cells. To directly compare a CXCR4-targeting treatment strategy with drugs that are currently used for stent coating, we studied the effects of the CXCR4 antagonist POL5551 and the drug sirolimus on neointima formation. Apolipoprotein E-deficient mice were treated with POL5551 or sirolimus continuously for 28 days after a carotid wire injury. POL5551 inhibited neointima formation by 63% (for a dosage of 2 mg/kg/day) and by 70% (for a dosage of 20 mg/kg/day). In comparison, sirolimus reduced the neointimal area by 69%. In contrast to treatment with POL5551 during the first three days after injury, injection of POL5551 (20 mg/kg) once per day for 28 days diminished neointimal hyperplasia by 53%. An analysis of the cellular composition of the neointima showed a reduction in the relative smooth muscle cell (SMC) and macrophage content in mice that had been treated with a high dose of POL5551. In contrast, the diminished SMC content after sirolimus treatment was associated with a neointimal enrichment of macrophages. Furthermore, endothelial recovery was impaired by sirolimus, but not by POL5551. Therefore, the inhibition of CXCR4 by POL5551 is equally effective in preventing neointima formation as sirolimus, but POL5551 might be more beneficial because treatment with it results in a more stable lesion phenotype and because it does not impair re-endothelialisation.