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Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice
- Source :
- Blood, Vol. 120, No 14 (2012) pp. 2879-2888
- Publication Year :
- 2012
- Publisher :
- American Society of Hematology, 2012.
-
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.
- Subjects :
- Male
Erythrocytes
Pyrazoles/pharmacology
Leukocytes/cytology/drug effects
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors/metabolism
Cell Communication
Pharmacology
Biochemistry
Mice
chemistry.chemical_compound
Vascular Diseases/chemically induced/drug therapy/metabolism
Antisickling Agents
Leukocytes
Antisickling Agents/therapeutic use
Hydroxyurea
Cell Adhesion/drug effects
Pyrimidines/pharmacology
Cyclic GMP
Cell adhesion molecule
Phosphodiesterase
Hematology
medicine.anatomical_structure
Endothelium, Vascular/cytology/drug effects/metabolism
Acute Disease
Female
Tumor necrosis factor alpha
Hydroxyurea/therapeutic use
Endothelium
Immunology
Leukocyte Rolling
Anemia, Sickle Cell
Biology
Erythrocytes/cytology/drug effects
Nitric oxide
Red Cells, Iron, and Erythropoiesis
Anemia, Sickle Cell/chemically induced/drug therapy/metabolism
Cell Adhesion
medicine
Animals
Humans
Vascular Diseases
Cell adhesion
Cyclic guanosine monophosphate
Tumor Necrosis Factor-alpha
Tumor Necrosis Factor-alpha/toxicity
Cell Biology
Mice, Inbred C57BL
Cyclic GMP/metabolism
Disease Models, Animal
Pyrimidines
chemistry
3',5'-Cyclic-AMP Phosphodiesterases
Pyrazoles
Endothelium, Vascular
Subjects
Details
- ISSN :
- 15280020 and 00064971
- Volume :
- 120
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi.dedup.....c83c94f5bdde182f2aafd109e4471a9b