Hydroxycarbamide decreases sickle reticulocyte adhesion to resting endothelium by inhibiting endothelial Lu/BCAM through phosphodiesterase 4A activation [Signal Transduction]

March 10th, 2014 by Chaar, V., Laurance, S., Lapoumeroulie, C., Cochet, S., De Grandis, M., Colin, Y., Elion, J., Le Van Kim, C., El Nemer, W.

Vaso-occlusive crises are the main acute complication in sickle cell disease. They are initiated by abnormal adhesion of circulating blood cells to vascular endothelium of the microcirculation. Several interactions involving an intricate network of adhesion molecules have been described between sickle red blood cells and the endothelial vascular wall. We have previously shown that young sickle reticulocytes adhere to resting endothelial cells through the interaction of α4β1 integrin with endothelial Lutheran/basal cell adhesion molecule (Lu/BCAM). In the present work, we investigated the functional impact of endothelial exposure to hydroxycarbamide (HC) on this interaction using transformed human bone marrow endothelial cells (TrHBMECs) and primary human pulmonary microvascular endothelial cells (HPMECs). Adhesion of sickle reticulocytes to HC-treated endothelial cells was decreased despite the HC-derived increase of Lu/BCAM expression. This was associated with decreased phosphorylation of Lu/BCAM and upregulation of the cAMP-specific phosphodiesterase 4A expression. Our study reveals a novel mechanism for HC in endothelial cells where it could modulate the function of membrane proteins through the regulation of PDE expression and cAMP-dependent signaling pathways.
  • Posted in Journal of Biological Chemistry, Publications
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