RGD Reference Report - Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice. - Rat Genome Database

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

Authors: Almeida, Camila Bononi  Scheiermann, Christoph  Jang, Jung-Eun  Prophete, Colette  Costa, Fernando Ferreira  Conran, Nicola  Frenette, Paul S 
Citation: Almeida CB, etal., Blood. 2012 Oct 4;120(14):2879-88. doi: 10.1182/blood-2012-02-409524. Epub 2012 Jul 25.
RGD ID: 242905184
Pubmed: PMID:22833547   (View Abstract at PubMed)
PMCID: PMC3466969   (View Article at PubMed Central)
DOI: DOI:10.1182/blood-2012-02-409524   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
PDE9AHumanVaso-occlusive Crisis treatmentISOPde9a (Mus musculus) RGD 
Pde9aRatVaso-occlusive Crisis treatmentISOPde9a (Mus musculus) RGD 
Pde9aMouseVaso-occlusive Crisis treatmentIMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Pde9a  (phosphodiesterase 9A)

Genes (Mus musculus)
Pde9a  (phosphodiesterase 9A)

Genes (Homo sapiens)
PDE9A  (phosphodiesterase 9A)


Additional Information