title: Decreased sickle red blood cell adhesion to laminin by hydroxyurea is associated with inhibition of Lu/BCAM protein phosphorylation.
abstract: Sickle cell disease is characterized by painful vaso-occlusive crises during which abnormal interactions between erythroid adhesion molecules and vessel-wall proteins are thought to play a critical role. Hydroxyurea, the only drug with proven benefit in sickle cell disease, diminishes these interactions, but its mechanism of action is not fully understood. We report that, under hydroxyurea, expression of the unique erythroid laminin receptor Lu/BCAM was increased, but red blood cell adhesion to laminin decreased. Because Lu/BCAM phosphorylation is known to activate cell adhesion to laminin, it was evaluated and found to be dramatically lower in hydroxyurea-treated patients. Analysis of the protein kinase A pathway showed decreased intracellular levels of the upstream effector cyclic adenosine monophosphate during hydroxyurea treatment. Using a cellular model expressing recombinant Lu/BCAM, we showed that hydroxyurea led to decreased intracellular cyclic adenosine monophosphate levels and diminished Lu/BCAM phosphorylation and cell adhesion. We provide evidence that hydroxyurea could reduce abnormal sickle red blood cell adhesion to the vascular wall by regulating the activation state of adhesion molecules independently of their expression level.
authors.affiliation: Inserm, Unité Mixte de Recherche en Santé 665, Paris, France.
authors.forename: Pablo
authors.initials: P
authors.lastname: Bartolucci
authors.forename: Vicky
authors.initials: V
authors.lastname: Chaar
authors.forename: Julien
authors.initials: J
authors.lastname: Picot
authors.forename: Dora
authors.initials: D
authors.lastname: Bachir
authors.forename: Anoosha
authors.initials: A
authors.lastname: Habibi
authors.forename: Christine
authors.initials: C
authors.lastname: Fauroux
authors.forename: Frédéric
authors.initials: F
authors.lastname: Galactéros
authors.forename: Yves
authors.initials: Y
authors.lastname: Colin
authors.forename: Caroline
authors.initials: C
authors.lastname: Le Van Kim
authors.forename: Wassim
authors.initials: W
authors.lastname: El Nemer
mesh_terms: D000755:Anemia, Sickle Cell / Q000097:blood*; D002448:Cell Adhesion / Q000187:drug effects*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D000242:Cyclic AMP / Q000032:analysis; D004913:Erythrocytes, Abnormal / Q000473:pathology*; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology*; D020014:K562 Cells; D007797:Laminin / Q000378:metabolism; D008188:Lutheran Blood-Group System / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects
chemical_list: C090228:BCAM protein, human; D015815:Cell Adhesion Molecules; D007797:Laminin; D008188:Lutheran Blood-Group System; D000242:Cyclic AMP; D006918:Hydroxyurea