1. Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice
- Author
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Camila B. Almeida, Jung Eun Jang, Nicola Conran, Christoph Scheiermann, Colette Prophete, Fernando Ferreira Costa, and Paul S. Frenette
- 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 - 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.
- Published
- 2012