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Type: Artigo de periódico
Title: Hydroxyurea And A Cgmp-amplifying Agent Have Immediate Benefits On Acute Vaso-occlusive Events In Sickle Cell Disease Mice.
Author: Almeida, Camila Bononi
Scheiermann, Christoph
Jang, Jung-Eun
Prophete, Colette
Costa, Fernando Ferreira
Conran, Nicola
Frenette, Paul S
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.
Subject: 3',5'-cyclic-amp Phosphodiesterases
Acute Disease
Anemia, Sickle Cell
Antisickling Agents
Cell Adhesion
Cell Communication
Cyclic Gmp
Disease Models, Animal
Endothelium, Vascular
Leukocyte Rolling
Mice, Inbred C57bl
Tumor Necrosis Factor-alpha
Vascular Diseases
Citation: Blood. v. 120, n. 14, p. 2879-88, 2012-Oct.
Rights: fechado
Identifier DOI: 10.1182/blood-2012-02-409524
Date Issue: 2012
Appears in Collections:Unicamp - Artigos e Outros Documentos

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