INSERM U1148, DHU FIRE, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France.
Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Département de Pathologie, Paris, France.
J Am Coll Cardiol. 2018 Jul 3;72(1):45-57. doi: 10.1016/j.jacc.2018.04.047.
The authors recently found that a CD31 agonist peptide reaches macrophages in injured aortas and exerts beneficial effects on apolipoprotein E-knockout (Apo E) mice subjected to angiotensin (Ang) II infusion, a model of experimental acute aortic dissection and intramural hematoma (ADIM).
The purpose of this study was to evaluate the therapeutic potential of a drug-suitable agonist peptide in experimental ADIM.
P8RI, a retro-inverso sequence of the best candidate identified by functional in vitro screening of a peptide library, passed an absorption, distribution, metabolism, excretion and toxicology analysis. Apo E mice (male, 28-week-old) implanted with Ang II-releasing pumps received P8RI (2.5 mg/kg/day) or vehicle from day 14 (n = 10/group). Leukocytes were analyzed by flow cytometry. Healing features of human and mouse dissected aortic segments were assessed by histology and immunofluorescence. The effect of CD31 on macrophages was evaluated using cells from CD31 mice and P8RI, in vitro.
Human and experimental ADIM were characterized by the infiltration of proinflammatory macrophages. The absence of CD31 enhanced the proinflammatory polarization of macrophages, whereas the CD31 agonist P8RI favored reparative macrophages both in vitro and in vivo. The administration of P8RI after the occurrence of ADIM prevented aneurysmal transformation by promoting the resolution of intramural hematoma and the production of collagen in dissected aortas in vivo, associated with enrichment of M2 macrophages at the site of injury.
CD31 signaling promotes the switching of proinflammatory macrophages to the reparative phenotype and favors the healing of experimental dissected aortas. Treatment with a drug-suitable CD31 agonist may facilitate the clinical management of ADIM.
作者最近发现，一种 CD31 激动肽可到达受损主动脉中的巨噬细胞，并对接受血管紧张素（Ang）II 输注的载脂蛋白 E 敲除（Apo E）小鼠产生有益影响，Ang II 输注是实验性急性主动脉夹层和壁内血肿（ADIM）的模型。
本研究旨在评估适合药物的激动肽在实验性 ADIM 中的治疗潜力。
P8RI 是通过对肽文库进行功能体外筛选鉴定的最佳候选物的反向序列，通过吸收、分布、代谢、排泄和毒理学分析。植入 Ang II 释放泵的 Apo E 小鼠（雄性，28 周龄）从第 14 天开始接受 P8RI（2.5mg/kg/天）或载体治疗（每组 n=10）。通过流式细胞术分析白细胞。通过组织学和免疫荧光评估人源和鼠源解剖主动脉段的愈合特征。使用 CD31 小鼠和 P8RI 评估 CD31 对巨噬细胞的影响，在体外。
人类和实验性 ADIM 的特征是促炎巨噬细胞的浸润。CD31 的缺失增强了巨噬细胞的促炎极化，而 CD31 激动肽 P8RI 既在体外也在体内促进了修复性巨噬细胞。ADIM 发生后给予 P8RI 可通过促进壁内血肿的消退和在体解剖主动脉中胶原的产生来预防动脉瘤形成，同时在损伤部位富集 M2 巨噬细胞。
CD31 信号转导促进促炎巨噬细胞向修复表型的转变，并有利于实验性解剖主动脉的愈合。使用适合药物的 CD31 激动肽治疗可能有助于 ADIM 的临床管理。
