Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice
| Autor: | Camila B. Almeida, Jung Eun Jang, Nicola Conran, Christoph Scheiermann, Colette Prophete, Fernando Ferreira Costa, Paul S. Frenette |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
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 |
| Zdroj: | Blood, Vol. 120, No 14 (2012) pp. 2879-2888 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2012-02-409524 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|