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: Stéphane M Camus, João A De Moraes, Philippe Bonnin, Paul Abbyad, Sylvain Le Jeune, François Lionnet, Laurent Loufrani, Linda Grimaud, Jean-Christophe Lambry, Dominique Charue, Laurent Kiger, Jean-Marie Renard, Claire Larroque, Hervé Le Clésiau, Alain Tedgui, Patrick Bruneval, Christina Barja-Fidalgo, Antigoni Alexandrou, Pierre-Louis Tharaux, Chantal M Boulanger, Olivier P Blanc-Brude
• Journal: Blood (Blood) Vol. 125 Issue 24 Pg. 3805-14 (Jun 11 2015) ISSN: 1528-0020 [Electronic] United States
• PMID: 25827830 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society of Hematology.

Chemical References

• Heme

Topics

• Anemia, Sickle Cell (blood, complications, metabolism, pathology)
• Animals
• Cell-Derived Microparticles (metabolism, pathology)
• Cohort Studies
• Endothelial Cells (metabolism, pathology)
• Erythrocytes (metabolism, pathology)
• Heme (metabolism)
• Hemolysis
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Oxidative Stress
• Vascular Diseases (blood, etiology, metabolism, pathology)