title: Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice.
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.
authors: Hematology and Hemotherapy Center, Instituto Nacional de Ciência e Tecnologia do Sangue (INCTS), UNICAMP, Campinas, São Paulo, Brazil.
authors: Camila Bononi
authors: CB
authors: Almeida
authors: Christoph
authors: C
authors: Scheiermann
authors: Jung-Eun
authors: JE
authors: Jang
authors: Colette
authors: C
authors: Prophete
authors: Fernando Ferreira
authors: FF
authors: Costa
authors: Nicola
authors: N
authors: Conran
authors: Paul S
authors: PS
authors: Frenette
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000208:Acute Disease; D000755:Anemia, Sickle Cell / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000986:Antisickling Agents / Q000627:therapeutic use*; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication; D006152:Cyclic GMP / Q000378:metabolism*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use*; D036904:Leukocyte Rolling; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity; D014652:Vascular Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000986:Antisickling Agents; C507056:BAY 73-6691; D011720:Pyrazoles; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C507055:Pde9a protein, mouse; D006152:Cyclic GMP; D006918:Hydroxyurea