Please use this identifier to cite or link to this item: http://repositorio.unicamp.br/jspui/handle/REPOSIP/200121
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
Animals
Antisickling Agents
Cell Adhesion
Cell Communication
Cyclic Gmp
Disease Models, Animal
Endothelium, Vascular
Erythrocytes
Female
Humans
Hydroxyurea
Leukocyte Rolling
Leukocytes
Male
Mice
Mice, Inbred C57bl
Pyrazoles
Pyrimidines
Tumor Necrosis Factor-alpha
Vascular Diseases
Rights: fechado
Identifier DOI: 10.1182/blood-2012-02-409524
Address: http://www.ncbi.nlm.nih.gov/pubmed/22833547
Date Issue: 2012
Appears in Collections:Artigos e Materiais de Revistas Científicas - Unicamp

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