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Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice

Almeida, Camila Bononi
Jang, Jung-Eun
Prophete, Colette
Costa, Fernando Ferreira
Conran, Nicola
Frenette, Paul S
Published in Blood. 2012, vol. 120, no. 14, p. 2879-2888
Abstract Inhibition of leukocyte adhesion to the vascular endothelium represents a novel and important approach for decreasing sickle cell disease (SCD) vaso-occlusion. Using a humanized SCD-mouse-model of tumor necrosis factor-α-induced acute vaso-occlusion, we herein present data demonstrating that short-term administration of either hydroxyurea or the phosphodiesterase 9 (PDE9) inhibitor, BAY73-6691, significantly altered leukocyte recruitment to the microvasculature. Notably, the administration of both agents led to marked improvements in leukocyte rolling and adhesion and decreased heterotypic red blood cell-leukocyte interactions, coupled with prolonged animal survival. Mechanistically, these rheologic benefits were associated with decreased endothelial adhesion molecule expression, as well as diminished leukocyte Mac-1-integrin activation and cyclic guanosine monophosphate (cGMP)-signaling, leading to reduced leukocyte recruitment. Our findings indicate that hydroxyurea has immediate beneficial effects on the microvasculature in acute sickle-cell crises that are independent of the drug's fetal hemoglobin-elevating properties and probably involve the formation of intravascular nitric oxide. In addition, inhibition of PDE9, an enzyme highly expressed in hematopoietic cells, amplified the cGMP-elevating effects of hydroxyurea and may represent a promising and more tissue-specific adjuvant therapy for this disease.
Keywords 3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors/metabolismAcute DiseaseAnemia, Sickle Cell/chemically induced/drug therapy/metabolismAnimalsAntisickling Agents/therapeutic useCell Adhesion/drug effectsCell CommunicationCyclic GMP/metabolismDisease Models, AnimalEndothelium, Vascular/cytology/drug effects/metabolismErythrocytes/cytology/drug effectsFemaleHumansHydroxyurea/therapeutic useLeukocyte RollingLeukocytes/cytology/drug effectsMaleMiceMice, Inbred C57BLPyrazoles/pharmacologyPyrimidines/pharmacologyTumor Necrosis Factor-alpha/toxicityVascular Diseases/chemically induced/drug therapy/metabolism
PMID: 22833547
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Research group L'influence du rôle du cycle circadien sur l'immunité (995)
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ALMEIDA, Camila Bononi et al. Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice. In: Blood, 2012, vol. 120, n° 14, p. 2879-2888. doi: 10.1182/blood-2012-02-409524

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Deposited on : 2019-01-31

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