Decreased sickle red blood cell adhesion to laminin by hydroxyurea is associated with inhibition of Lu/BCAM protein phosphorylation.
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.
Bartolucci
Pablo
P
Inserm, Unité Mixte de Recherche en Santé 665, Paris, France.
Chaar
Vicky
V
Picot
Julien
J
Bachir
Dora
D
Habibi
Anoosha
A
Fauroux
Christine
C
Galactéros
Frédéric
F
Colin
Yves
Y
Le Van Kim
Caroline
C
El Nemer
Wassim
W
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
C090228:BCAM protein, human; D015815:Cell Adhesion Molecules; D007797:Laminin; D008188:Lutheran Blood-Group System; D000242:Cyclic AMP; D006918:Hydroxyurea