Macrophage CD31 Signaling in Dissecting Aortic Aneurysm
Macrophage CD31 Signaling in Dissecting Aortic Aneurysm
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DOI：
10.1016/j.jacc.2018.04.047
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发表时间：
2018-07-03
影响因子：
24
通讯作者：
Caligiuri, Giuseppina
中科院分区：
文献类型：
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作者：
Andreata, Francesco;Syvannarath, Varouna;Caligiuri, Giuseppina
作者最近发现，CD 31激动剂肽可到达损伤的动脉中的巨噬细胞，并对载脂蛋白E基因敲除发挥有益作用接受血管紧张素（Ang）II输注的（Apo E -/-）小鼠，实验性急性主动脉夹层和壁内血肿（ADIM）模型。目的本研究的目的是评估药物的治疗潜力-方法通过体外肽库功能筛选，筛选出最佳候选肽P8 RI，并对其进行吸收、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P8 RI（2.5 mg/kg/天）或溶媒（n = 10/组）。通过流式细胞术分析白细胞。通过组织学和免疫荧光法评估人类和小鼠主动脉夹层段的愈合特征。用CD 31（-/-）小鼠细胞和P8 RI细胞体外研究CD 31对巨噬细胞的影响。在体外和体内，CD 31的缺乏增强了巨噬细胞的促炎性极化，而CD 31激动剂P8 RI有利于修复性巨噬细胞。ADIM发生后的P8 RI的管理，防止通过促进壁内血肿的决议和胶原蛋白的生产在解剖arthritas在体内，与富集的M2巨噬细胞在该网站的injuries.CONCLUSIONS CD 31信号促进开关的促炎性巨噬细胞的修复表型，有利于实验解剖arthritas的愈合。使用药物合适的CD 31激动剂治疗可能有助于ADIM的临床管理。(C)2018年由美国心脏病学会基金会。
BACKGROUND 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).OBJECTIVES The purpose of this study was to evaluate the therapeutic potential of a drug-suitable agonist peptide in experimental ADIM.METHODS 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-weekold) 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.RESULTS 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.CONCLUSIONS 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. (C) 2018 by the American College of Cardiology Foundation.