Macrophage CD 31 Signaling in Dissecting Aortic Aneurysm

ISS Fro Hô Hô con Re de [Co Sy Na col rec rel Ma 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 1⁄4 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. (J Am Coll Cardiol 2018;72:45–57) © 2018 by the American College of Cardiology Foundation. A cute aortic dissection and intramural hematoma (ADIM) (dissecting aneurysm) is a lifethreatening disease with a mortality of 50% within the first 48 h. In the absence of involvement N 0735-1097/$36.00 m the INSERM U1148, DHU FIRE, Université Paris Diderot, PRES Sorbo pitaux de Paris, Hôpital Bichat, Département de Pathologie, Paris, Franc pital Bichat, Service de Cardiologie et de Physiologie, Paris, France. *D tributed equally to this work and are joint first authors. This study was search Agency (ANR-08-EBIO-04 “BROSCI”; ANR-14-CE17-0014 “IMPLAN France” (FDF 2008-002724), Fondation pour la Recherche Médicale (DBS2 POC 2013 and 2014]), European Commission (FP7-HEALTH-2013-INN vannarath is the recipient of a doctoral grant “CIFRE” (Convention industr tional Research and Technology association (ANRT) and funded by the laborative research agreement with Inserm-Transfert, N 140830/12026B10 ipients of a doctoral grant from the Region Ile de France (CORDDIM). All a evant to the contents of this paper to disclose. nuscript received March 23, 2018; accepted April 12, 2018. of the ascending aorta, the clinical management is essentially palliative and is directed at reducing the systemic blood pressure and heart rate as much as possible, which limits the propagation of the false https://doi.org/10.1016/j.jacc. 2018.04. 047 nne Paris Cite, Paris, France; Assistance Publiquee; and the Assistance Publique-Hôpitaux de Paris, rs. Andreata, Syvannarath, Clement, and Delbosc funded in part by grants from the French National TS”; DS0404-16-RHUS-00010 “iVASC”), “Fondation 014090764), Fondation de l’Avenir, Inserm-Transfert OVATION603131 “VIA”), Bruxelles, Belgium. Dr. ielle de formation par la recherche) from the French Institut de Recherche Servier (“Avenant 1” of the ), Paris, France. Drs. Andreata and Clement were the uthors have reported that they have no relationships ABBR EV I A T I ON S AND ACRONYMS ADIM = acute aortic dissection and intramural hematoma Ang II = angiotensin II Apo E / = apolipoprotein E knockout BMDM = bone marrow–derived macrophage