Author + information
- Received March 23, 2018
- Accepted April 12, 2018
- Published online June 25, 2018.
- Francesco Andreata, PhDa,∗,
- Varouna Syvannarath, MSca,∗,
- Marc Clement, PhDa,∗,
- Sandrine Delbosc, PhDa,∗,
- Kevin Guedj, PhDa,
- Giulia Fornasa, PhDa,
- Jamila Khallou-Laschet, PhDa,
- Marion Morvan, BSca,
- Guillaume Even, BSca,
- Emanuele Procopio, MSca,
- Anh-Thu Gaston, BSca,
- Marie Le Borgne, PhDa,
- Lydia Deschamps, MD, PhDb,
- Antonino Nicoletti, PhDa and
- Giuseppina Caligiuri, MD, PhDa,c,∗ (, )@Inserm
- aINSERM U1148, DHU FIRE, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France
- bAssistance Publique-Hôpitaux de Paris, Hôpital Bichat, Département de Pathologie, Paris, France
- cAssistance Publique-Hôpitaux de Paris, Hôpital Bichat, Service de Cardiologie et de Physiologie, Paris, France
- ↵∗Address for correspondence:
Dr. Giuseppina Caligiuri, INSERM U1148, University Hospital Bichat, 46 rue Henri Huchard, F-75018 Paris, France.
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-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.
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.
↵∗ Drs. Andreata, Syvannarath, Clement, and Delbosc contributed equally to this work and are joint first authors.
This study was funded in part by grants from the French National Research Agency (ANR-08-EBIO-04 “BROSCI”; ANR-14-CE17-0014 “IMPLANTS”; DS0404-16-RHUS-00010 “iVASC”), “Fondation de France” (FDF 2008-002724), Fondation pour la Recherche Médicale (DBS2014090764), Fondation de l’Avenir, Inserm-Transfert [CoPOC 2013 and 2014]), European Commission (FP7-HEALTH-2013-INNOVATION- 603131 “VIA”), Bruxelles, Belgium. Dr. Syvannarath is the recipient of a doctoral grant “CIFRE” (Convention industrielle de formation par la recherche) from the French National Research and Technology association (ANRT) and funded by the Institut de Recherche Servier (“Avenant 1” of the collaborative research agreement with Inserm-Transfert, N˚ 140830/12026B10), Paris, France. Drs. Andreata and Clement were the recipients of a doctoral grant from the Region Ile de France (CORDDIM). All authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received March 23, 2018.
- Accepted April 12, 2018.
- 2018 American College of Cardiology Foundation
This article requires a subscription or purchase to view the full text. If you are a subscriber or member, click Login or the Subscribe link (top menu above) to access this article.