Novel epinephrine and cyclic AMP-mediated activation of BCAM/Lu-dependent sickle (SS) RBC adhesion

The vasoocclusive crisis is the major clinical feature of sickle cell anemia, which is believed to be initiated or sustained by sickle (SS) red blood cell (RBC) adhesion to the vascular wall. SS RBCs, but not unaffected (AA) RBCs, adhere avidly to multiple components of the vascular wall, including...

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Bibliographic Details
Published in:Blood 2003-04, Vol.101 (8), p.3281-3287
Main Authors: Hines, Patrick C., Zen, Qin, Burney, Sharran N., Shea, Deborah A., Ataga, Kenneth I., Orringer, Eugene P., Telen, Marilyn J., Parise, Leslie V.
Format: Article
Language:English
Subjects:
Anemia, Sickle Cell - blood
Anemias. Hemoglobinopathies
Biological and medical sciences
Blood Cell Count
Cell Adhesion - drug effects
Cell Adhesion Molecules - pharmacology
Cell Adhesion Molecules - physiology
Colforsin - pharmacology
Cyclic AMP - classification
Cyclic AMP - physiology
Cyclic AMP-Dependent Protein Kinases - blood
Diseases of red blood cells
Epinephrine - pharmacology
Erythrocyte Aggregation - drug effects
Erythrocytes, Abnormal - cytology
Erythrocytes, Abnormal - drug effects
Hematologic and hematopoietic diseases
Humans
Laminin - metabolism
Lutheran Blood-Group System
Medical sciences
Neoplasm Proteins - pharmacology
Neoplasm Proteins - physiology
Protein Isoforms - metabolism
Receptors, Adrenergic, beta-2 - physiology
Recombinant Proteins - pharmacology
Reticulocytes
Second Messenger Systems - drug effects
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Summary:The vasoocclusive crisis is the major clinical feature of sickle cell anemia, which is believed to be initiated or sustained by sickle (SS) red blood cell (RBC) adhesion to the vascular wall. SS RBCs, but not unaffected (AA) RBCs, adhere avidly to multiple components of the vascular wall, including laminin. Here we report a novel role for epinephrine and cyclic adenosine monophosphate (cAMP) in the regulation of human SS RBC adhesiveness via the laminin receptor, basal cell adhesion molecule/Lutheran (BCAM/Lu). Our data demonstrate that peripheral SS RBCs contain greater than 4-fold more cAMP than AA RBCs under basal conditions. Forskolin or the stress mediator epinephrine further elevates cAMP in SS RBCs and increases adhesion of SS RBCs to laminin in a protein kinase A (PKA)–dependent manner, with the low-density population being the most responsive. Epinephrine-stimulated adhesion to laminin, mediated primarily via the β2-adrenergic receptor, occurred in SS RBC samples from 46% of patients and was blocked by recombinant, soluble BCAM/Lu, implicating this receptor as a target of cAMP signaling. Thus, these studies demonstrate a novel, rapid regulation of SS RBC adhesion by a cAMP-dependent pathway and suggest that components of this pathway, particularly PKA, the β2-adrenergic receptor, and BCAM/Lu, should be further explored as potential therapeutic targets to inhibit SS RBC adhesion.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2001-12-0289