title: Circulating cell membrane microparticles transfer heme to endothelial cells and trigger vasoocclusions in sickle cell disease.
abstract: Intravascular hemolysis describes the relocalization of heme and hemoglobin (Hb) from erythrocytes to plasma. We investigated the concept that erythrocyte membrane microparticles (MPs) concentrate cell-free heme in human hemolytic diseases, and that heme-laden MPs have a physiopathological impact. Up to one-third of cell-free heme in plasma from 47 patients with sickle cell disease (SCD) was sequestered in circulating MPs. Erythrocyte vesiculation in vitro produced MPs loaded with heme. In silico analysis predicted that externalized phosphatidylserine (PS) in MPs may associate with and help retain heme at the cell surface. Immunohistology identified Hb-laden MPs adherent to capillary endothelium in kidney biopsies from hyperalbuminuric SCD patients. In addition, heme-laden erythrocyte MPs adhered and transferred heme to cultured endothelial cells, inducing oxidative stress and apoptosis. In transgenic SAD mice, infusion of heme-laden MPs triggered rapid vasoocclusions in kidneys and compromised microvascular dilation ex vivo. These vascular effects were largely blocked by heme-scavenging hemopexin and by the PS antagonist annexin-a5, in vitro and in vivo. Adversely remodeled MPs carrying heme may thus be a source of oxidant stress for the endothelium, linking hemolysis to vascular injury. This pathway might provide new targets for the therapeutic preservation of vascular function in SCD.
authors.affiliation: Paris Center for Cardiovascular Research, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche-970, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, and Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors.forename: Stéphane M
authors.initials: SM
authors.lastname: Camus
authors.affiliation: Paris Center for Cardiovascular Research, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche-970, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, and Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors.forename: João A
authors.initials: JA
authors.lastname: De Moraes
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U965, Université Paris Diderot, Sorbonne Paris Cité, and Physiologie Clinique-Explorations-Fonctionnelles, Hôpital Lariboisière, AP-HP, Paris, France;
authors.forename: Philippe
authors.initials: P
authors.lastname: Bonnin
authors.affiliation: Optics and Biosciences Laboratory, Institut National de la Santé et de la Recherche Médicale U696, and Ecole Polytechnique, Palaiseau, France;
authors.forename: Paul
authors.initials: P
authors.lastname: Abbyad
authors.affiliation: Service de Médecine Interne et Hypertension Artérielle, Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, Bobigny, France;
authors.forename: Sylvain
authors.initials: S
authors.lastname: Le Jeune
authors.affiliation: Service de Médecine Interne, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France;
authors.forename: François
authors.initials: F
authors.lastname: Lionnet
authors.affiliation: Department of Integrated Neurovascular Biology, Institut National de la Santé et de la Recherche Médicale U771, Centre National de la Recherche Scientifique Unité Mixte de Recherche 6214, and Université d'Angers, Angers, France;
authors.forename: Laurent
authors.initials: L
authors.lastname: Loufrani
authors.affiliation: Department of Integrated Neurovascular Biology, Institut National de la Santé et de la Recherche Médicale U771, Centre National de la Recherche Scientifique Unité Mixte de Recherche 6214, and Université d'Angers, Angers, France;
authors.forename: Linda
authors.initials: L
authors.lastname: Grimaud
authors.affiliation: Optics and Biosciences Laboratory, Institut National de la Santé et de la Recherche Médicale U696, and Ecole Polytechnique, Palaiseau, France;
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Lambry
authors.affiliation: Paris Center for Cardiovascular Research, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche-970, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, and Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors.forename: Dominique
authors.initials: D
authors.lastname: Charue
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U955, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Créteil and Universités Paris VI and XI, Paris, France;
authors.forename: Laurent
authors.initials: L
authors.lastname: Kiger
authors.affiliation: Paris Center for Cardiovascular Research, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche-970, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, and Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Renard
authors.affiliation: Centre d'Examens de Santé, Caisse Primaire d'Assurance Maladie Seine St Denis, Bobigny, France; and.
authors.forename: Claire
authors.initials: C
authors.lastname: Larroque
authors.affiliation: Centre d'Examens de Santé, Caisse Primaire d'Assurance Maladie Seine St Denis, Bobigny, France; and.
authors.forename: Hervé
authors.initials: H
authors.lastname: Le Clésiau
authors.affiliation: Paris Center for Cardiovascular Research, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche-970, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, and Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors.forename: Alain
authors.initials: A
authors.lastname: Tedgui
authors.affiliation: Paris Center for Cardiovascular Research, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche-970, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, and Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors.forename: Patrick
authors.initials: P
authors.lastname: Bruneval
authors.affiliation: Departamento de Biologia Celular e Genética, Instituto de Biologia Roberto Alcântara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Christina
authors.initials: C
authors.lastname: Barja-Fidalgo
authors.affiliation: Optics and Biosciences Laboratory, Institut National de la Santé et de la Recherche Médicale U696, and Ecole Polytechnique, Palaiseau, France;
authors.forename: Antigoni
authors.initials: A
authors.lastname: Alexandrou
authors.affiliation: Paris Center for Cardiovascular Research, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche-970, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, and Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors.forename: Pierre-Louis
authors.initials: PL
authors.lastname: Tharaux
authors.affiliation: Paris Center for Cardiovascular Research, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche-970, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, and Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors.forename: Chantal M
authors.initials: CM
authors.lastname: Boulanger
authors.affiliation: Paris Center for Cardiovascular Research, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche-970, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, and Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors.forename: Olivier P
authors.identifier: http://orcid.org/0000-0002-4015-0615
authors.initials: OP
authors.lastname: Blanc-Brude
mesh_terms: D000755:Anemia, Sickle Cell / Q000097:blood / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D055252:Cell-Derived Microparticles / Q000378:metabolism / Q000473:pathology*; D015331:Cohort Studies; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D004912:Erythrocytes / Q000378:metabolism / Q000473:pathology; D006418:Heme / Q000378:metabolism*; D006461:Hemolysis; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D014652:Vascular Diseases / Q000097:blood / Q000209:etiology* / Q000378:metabolism / Q000473:pathology
chemical_list: D006418:Heme
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