Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice

dc.creatorAlmeida, CB
dc.creatorScheiermann, C
dc.creatorJang, JE
dc.creatorProphete, C
dc.creatorCosta, FF
dc.creatorConran, N
dc.creatorFrenette, PS
dc.date2012
dc.dateOCT 4
dc.date2014-07-30T17:59:46Z
dc.date2015-11-26T16:49:28Z
dc.date2014-07-30T17:59:46Z
dc.date2015-11-26T16:49:28Z
dc.date.accessioned2018-03-28T23:36:12Z
dc.date.available2018-03-28T23:36:12Z
dc.identifierBlood. Amer Soc Hematology, v. 120, n. 14, n. 2879, n. 2888, 2012.
dc.identifier0006-4971
dc.identifierWOS:000311616900020
dc.identifier10.1182/blood-2012-02-409524
dc.identifierhttp://www.repositorio.unicamp.br/jspui/handle/REPOSIP/69043
dc.identifierhttp://repositorio.unicamp.br/jspui/handle/REPOSIP/69043
dc.identifier.urihttp://repositorioslatinoamericanos.uchile.cl/handle/2250/1275465
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionInhibition 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)
dc.description120
dc.description14
dc.description2879
dc.description2888
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionGerman Academic Exchange Service (DAAD)
dc.descriptionNational Institutes of Health [R01HL69438, R01HL097700, RC1HL099545]
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionFAPESP [Proc 07/58533-3, Proc 11/50959-7]
dc.descriptionNational Institutes of Health [R01HL69438, R01HL097700, RC1HL099545]
dc.languageen
dc.publisherAmer Soc Hematology
dc.publisherWashington
dc.publisherEUA
dc.relationBlood
dc.relationBlood
dc.rightsfechado
dc.sourceWeb of Science
dc.subjectInhaled Nitric-oxide
dc.subjectSoluble Guanylyl Cyclase
dc.subjectAdherent Leukocytes
dc.subjectErythroid-cells
dc.subjectMouse Model
dc.subjectE-selectin
dc.subjectHemoglobin
dc.subjectExpression
dc.subjectTherapy
dc.subjectAnemia
dc.titleHydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice
dc.typeArtículos de revistas


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