Role of nitric oxide and the cyclic guanosine monophosphate dependent patway on the adhesive properties leucocytes of sickle cell disease patients / Ação do oxido nitrico e da via dependente de guanosina monofosfato ciclico nas propriedades adesivas de leucocitos de pacientes com anemia falciforme

AUTOR(ES)
DATA DE PUBLICAÇÃO

2008

RESUMO

Increased leukocyte adhesion to vascular endothelium contributes to vaso-occlusion in sickle cell disease (SCD). Since nitric oxide (NO) bioavailability is decreased in SCD and NO may inhibit leukocyte adhesion, we determined whether stimulation of NO-signalling pathways can decrease the adhesive properties of neutrophils from SCD individuals (SCDneu). SCDneu presented greater adhesion, in vitro, to both fibronectin (FN) and ICAM-1 than control neutrophils; co-incubation of SCDneu with the NO-donor agents, sodium nitroprusside (SNP) and dietheylamine NONOate (DEANO), and the guanylate cyclase stimulator, BAY41-2272, all significantly diminished increased adhesion to FN/ICAM-1. Oxadiazolo[4,3-a]quinoxalin-1-one, a guanylate cyclase inhibitor, reversed SNP/DEANO-diminished adhesion to FN, implicating cGMP-dependent signalling in this mechanism. Interestingly, intracellular cGMP was significantly higher in neutrophils from SCD individuals on hydroxyurea (SCDHUneu) and, accordingly, SCDHUneu adhesion to FN/ICAM-1 was significantly lower than that of SCDneu. In addition, co-incubation of SCDneu with KT5720 (an inhibitor of PKA), but not KT5823 (inhibitor of PKG), abrogated increased basal SCDneu adhesion. Stimulation of SCDneu with IL-8 also significantly augmented SCDneu adhesion to FN and this increase in adhesion was abolished by KT5720. Data indicate that up-regulated cAMP signalling plays a significant role in altered adhesive properties in SCDneu. Such alterations may have significant implications for the pathophysiology of the disease and the cAMP-PKA pathway may represent a therapeutic target for the abrogation of altered leukocyte function. Agents that stimulate the NO/cGMP-dependent pathway may have beneficial effects on leukocyte function if used in these individuals.

ASSUNTO(S)

nitric oxide oxido nitrico anemia falciforme adhesion leucocytes leucocitos adesão sickle cell anemia

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