Artículos de revistas
Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice
Registro en:
Blood. Amer Soc Hematology, v. 120, n. 14, n. 2879, n. 2888, 2012.
0006-4971
WOS:000311616900020
10.1182/blood-2012-02-409524
Autor
Almeida, CB
Scheiermann, C
Jang, JE
Prophete, C
Costa, FF
Conran, N
Frenette, PS
Institución
Resumen
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) 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-alpha-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. (Blood. 2012; 120(14): 2879-2888) 120 14 2879 2888 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) German Academic Exchange Service (DAAD) National Institutes of Health [R01HL69438, R01HL097700, RC1HL099545] Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) FAPESP [Proc 07/58533-3, Proc 11/50959-7] National Institutes of Health [R01HL69438, R01HL097700, RC1HL099545]