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

Camila Bononi Almeida, Christoph Scheiermann, Jung Eun Jang, Colette M. Prophete, Fernando Ferreira Costa, Nicola Conran, Paul S. Frenette

Research output: Contribution to journalArticle

47 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2879-2888
Number of pages10
JournalBlood
Volume120
Issue number14
DOIs
StatePublished - Oct 4 2012

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Hydroxyurea
Cyclic GMP
Sickle Cell Anemia
Leukocytes
Adhesion
Phosphoric Diester Hydrolases
Fetal Hemoglobin
Microvessels
Integrins
Leukocyte Rolling
Nitric Oxide
Animals
Blood
Tumor Necrosis Factor-alpha
Chemical activation
Cells
Phosphodiesterase Inhibitors
Tissue
Vascular Endothelium
Molecules

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

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

In: Blood, Vol. 120, No. 14, 04.10.2012, p. 2879-2888.

Research output: Contribution to journalArticle

Almeida, Camila Bononi ; Scheiermann, Christoph ; Jang, Jung Eun ; Prophete, Colette M. ; Costa, Fernando Ferreira ; Conran, Nicola ; Frenette, Paul S. / Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice. In: Blood. 2012 ; Vol. 120, No. 14. pp. 2879-2888.
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