title: Hydroxycarbamide decreases sickle reticulocyte adhesion to resting endothelium by inhibiting endothelial lutheran/basal cell adhesion molecule (Lu/BCAM) through phosphodiesterase 4A activation.
abstract: Vaso-occlusive crises are the main acute complication in sickle cell disease. They are initiated by abnormal adhesion of circulating blood cells to vascular endothelium of the microcirculation. Several interactions involving an intricate network of adhesion molecules have been described between sickle red blood cells and the endothelial vascular wall. We have shown previously that young sickle reticulocytes adhere to resting endothelial cells through the interaction of α4β1 integrin with endothelial Lutheran/basal cell adhesion molecule (Lu/BCAM). In the present work, we investigated the functional impact of endothelial exposure to hydroxycarbamide (HC) on this interaction using transformed human bone marrow endothelial cells and primary human pulmonary microvascular endothelial cells. Adhesion of sickle reticulocytes to HC-treated endothelial cells was decreased despite the HC-derived increase of Lu/BCAM expression. This was associated with decreased phosphorylation of Lu/BCAM and up-regulation of the cAMP-specific phosphodiesterase 4A expression. Our study reveals a novel mechanism for HC in endothelial cells where it could modulate the function of membrane proteins through the regulation of phosphodiesterase expression and cAMP-dependent signaling pathways.
authors.affiliation: INSERM, U1134, F-75739 Paris, France,; Université Paris Diderot, Sorbonne Paris Cité, UMR_S 1134, F-75739 Paris, France,; Institut National de la Transfusion Sanguine, F-75739 Paris, France,; Laboratoire d'Excellence GR-Ex, F-75238 Paris, France, and.
authors.forename: Vicky
authors.initials: V
authors.lastname: Chaar
authors.affiliation: INSERM, U1134, F-75739 Paris, France,; Université Paris Diderot, Sorbonne Paris Cité, UMR_S 1134, F-75739 Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Laurance
authors.affiliation: INSERM, U1134, F-75739 Paris, France,; Université Paris Diderot, Sorbonne Paris Cité, UMR_S 1134, F-75739 Paris, France,; Laboratoire d'Excellence GR-Ex, F-75238 Paris, France, and.
authors.forename: Claudine
authors.initials: C
authors.lastname: Lapoumeroulie
authors.affiliation: INSERM, U1134, F-75739 Paris, France,; Université Paris Diderot, Sorbonne Paris Cité, UMR_S 1134, F-75739 Paris, France,; Institut National de la Transfusion Sanguine, F-75739 Paris, France,; Laboratoire d'Excellence GR-Ex, F-75238 Paris, France, and.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Cochet
authors.affiliation: INSERM, U1134, F-75739 Paris, France,; Université Paris Diderot, Sorbonne Paris Cité, UMR_S 1134, F-75739 Paris, France,; Institut National de la Transfusion Sanguine, F-75739 Paris, France,; Laboratoire d'Excellence GR-Ex, F-75238 Paris, France, and.
authors.forename: Maria
authors.initials: M
authors.lastname: De Grandis
authors.affiliation: INSERM, U1134, F-75739 Paris, France,; Université Paris Diderot, Sorbonne Paris Cité, UMR_S 1134, F-75739 Paris, France,; Institut National de la Transfusion Sanguine, F-75739 Paris, France,; Laboratoire d'Excellence GR-Ex, F-75238 Paris, France, and.
authors.forename: Yves
authors.initials: Y
authors.lastname: Colin
authors.affiliation: INSERM, U1134, F-75739 Paris, France,; Université Paris Diderot, Sorbonne Paris Cité, UMR_S 1134, F-75739 Paris, France,; Laboratoire d'Excellence GR-Ex, F-75238 Paris, France, and; Assistance Publique-Hôpitaux de Paris, Département de Génétique, Hôpital Robert Debré, Paris F-75019, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Elion
authors.affiliation: INSERM, U1134, F-75739 Paris, France,; Université Paris Diderot, Sorbonne Paris Cité, UMR_S 1134, F-75739 Paris, France,; Institut National de la Transfusion Sanguine, F-75739 Paris, France,; Laboratoire d'Excellence GR-Ex, F-75238 Paris, France, and.
authors.forename: Caroline
authors.initials: C
authors.lastname: Le Van Kim
authors.affiliation: INSERM, U1134, F-75739 Paris, France,; Université Paris Diderot, Sorbonne Paris Cité, UMR_S 1134, F-75739 Paris, France,; Institut National de la Transfusion Sanguine, F-75739 Paris, France,; Laboratoire d'Excellence GR-Ex, F-75238 Paris, France, and. Electronic address: wassim.el-nemer@inserm.fr.
authors.forename: Wassim
authors.initials: W
authors.lastname: El Nemer
mesh_terms: D000755:Anemia, Sickle Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000986:Antisickling Agents / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000096:biosynthesis* / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology*; D020014:K562 Cells; D008188:Lutheran Blood-Group System / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D012156:Reticulocytes / Q000378:metabolism* / Q000473:pathology; D015290:Second Messenger Systems / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D000986:Antisickling Agents; C090228:BCAM protein, human; D015815:Cell Adhesion Molecules; D008188:Lutheran Blood-Group System; D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517355:PDE4A protein, human; D006918:Hydroxyurea
keywords: Adhesion; Blood; Cell Signaling; Endothelial Cell; Hydroxycarbamide; Lu/BCAM; Protein Phosphorylation; Sickle Cell Disease