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 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 beta 2-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 beta 2-adrenergic receptor, and BCAM/Lu, should be further explored as potential therapeutic targets to inhibit SS RBC adhesion.
Hines
Patrick C
PC
Department of Pharmacology, University of North Carolina at Chapel Hill, 27599, USA.
Zen
Qin
Q
Burney
Sharran N
SN
Shea
Deborah A
DA
Ataga
Kenneth I
KI
Orringer
Eugene P
EP
Telen
Marilyn J
MJ
Parise
Leslie V
LV
D000755:Anemia, Sickle Cell / Q000097:blood*; D001772:Blood Cell Count; D002448:Cell Adhesion / Q000187:drug effects*; D015815:Cell Adhesion Molecules / Q000494:pharmacology / Q000502:physiology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000145:classification / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000097:blood; D004837:Epinephrine / Q000494:pharmacology*; D004903:Erythrocyte Aggregation / Q000187:drug effects*; D004913:Erythrocytes, Abnormal / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008188:Lutheran Blood-Group System; D009363:Neoplasm Proteins / Q000494:pharmacology / Q000502:physiology*; D020033:Protein Isoforms / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D012156:Reticulocytes; D015290:Second Messenger Systems / Q000187:drug effects*
C090228:BCAM protein, human; D015815:Cell Adhesion Molecules; D007797:Laminin; D008188:Lutheran Blood-Group System; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D018343:Receptors, Adrenergic, beta-2; D011994:Recombinant Proteins; C119013:laminin 10; C474559:laminin 11 protein, human; D005576:Colforsin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D004837:Epinephrine