Epinephrine acts through erythroid signaling pathways to activate sickle cell adhesion to endothelium via LW-alphavbeta3 interactions.
The possible role of physiologic stress hormones in enhancing adhesion of sickle erythrocytes (SS RBCs) to endothelial cells (ECs) in sickle cell disease (SCD) has not been previously explored. We have now found that up-regulation of intracellular cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) by epinephrine significantly increased sickle but not normal erythrocyte adhesion to both primary and immortalized ECs. Inhibition of serine/threonine phosphatases also enhanced sickle erythrocyte adhesion at least partially through a PKA-dependent mechanism. Adhesion was mediated through LW (intercellular adhesion molecule-4 [ICAM-4], CD242) blood group glycoprotein, and immunoprecipitation studies showed that LW on sickle but not on normal erythrocytes undergoes increased PKA-dependent serine phosphorylation as a result of activation. The major counter receptor for LW was identified as the alphavbeta3 integrin on ECs. These data suggest that adrenergic hormones such as epinephrine may initiate or exacerbate vaso-occlusion and thus contribute to the association of vaso-occlusive events with physiologic stress.
Division of Hematology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Rahima
R
Zennadi
Patrick C
PC
Hines
Laura M
LM
De Castro
Jean-Pierre
JP
Cartron
Leslie V
LV
Parise
Marilyn J
MJ
Telen
D000755:Anemia, Sickle Cell / Q000097:blood* / Q000150:complications / Q000473:pathology; D016022:Case-Control Studies; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases; D004730:Endothelium, Vascular / Q000473:pathology*; D004837:Epinephrine / Q000494:pharmacology*; D004913:Erythrocytes, Abnormal / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D014471:Umbilical Veins; D014652:Vascular Diseases / Q000209:etiology
D015815:Cell Adhesion Molecules; C095100:ICAM4 protein, human; D039302:Integrin alphaVbeta3; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D004837:Epinephrine