Circulating cell membrane microparticles transfer heme to endothelial cells and trigger vasoocclusions in sickle cell disease

• Published in: Blood Vol. 125; no. 24; pp. 3805 - 3814
• Main Authors: Camus, Stéphane M., De Moraes, João A., Bonnin, Philippe, Abbyad, Paul, Le Jeune, Sylvain, Lionnet, François, Loufrani, Laurent, Grimaud, Linda, Lambry, Jean-Christophe, Charue, Dominique, Kiger, Laurent, Renard, Jean-Marie, Larroque, Claire, Le Clésiau, Hervé, Tedgui, Alain, Bruneval, Patrick, Barja-Fidalgo, Christina, Alexandrou, Antigoni, Tharaux, Pierre-Louis, Boulanger, Chantal M., Blanc-Brude, Olivier P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11-06-2015; American Society of Hematology
• Subjects: Anemia, Sickle Cell - blood; Anemia, Sickle Cell - complications; Anemia, Sickle Cell - metabolism; Anemia, Sickle Cell - pathology; Animals; Cell-Derived Microparticles - metabolism; Cell-Derived Microparticles - pathology; Cellular Biology; Cohort Studies; Endothelial Cells - metabolism; Endothelial Cells - pathology; Erythrocytes - metabolism; Erythrocytes - pathology; Hematology; Heme - metabolism; Hemolysis; Human health and pathology; Humans; Life Sciences; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Vascular Biology; Vascular Diseases - blood; Vascular Diseases - etiology; Vascular Diseases - metabolism; Vascular Diseases - pathology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2014-07-589283

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.
•A significant fraction of cell-free heme in plasma is contained in circulating erythrocyte MPs, particularly during hemolysis.•Heme-laden MPs can transfer heme to vascular endothelium and mediate oxidative stress, vascular dysfunction, and vasoocclusions.