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Beneficial Effects of Soluble Guanylyl Cyclase Stimulation and Activation in Sickle Cell Disease Are Amplified by Hydroxyurea: In Vitro and In Vivo Studies

Ferreira, W.A. ; Chweih, H. ; Lanaro, C. ; Almeida, C.B. ; Brito, P.L. ; Gotardo, E.M.F. ; Torres, L. ; Miguel, L.I. ; Franco-Penteado, C.F. ; Leonardo, F.C. ; Garcia, F. ; Saad, S.T.O. ; Frenette, P.S. ; Brockschnieder, D. ; Costa, F.F. ; Stasch, J.P. ; Sandner, P. ; Conran, N.

The Journal of pharmacology and experimental therapeutics, 2020-09, Vol.374 (3), p.469-478 [Periódico revisado por pares]

Bethesda, MD: The American Society for Pharmacology and Experimental Therapeutics

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  • Título:
    Beneficial Effects of Soluble Guanylyl Cyclase Stimulation and Activation in Sickle Cell Disease Are Amplified by Hydroxyurea: In Vitro and In Vivo Studies
  • Autor: Ferreira, W.A. ; Chweih, H. ; Lanaro, C. ; Almeida, C.B. ; Brito, P.L. ; Gotardo, E.M.F. ; Torres, L. ; Miguel, L.I. ; Franco-Penteado, C.F. ; Leonardo, F.C. ; Garcia, F. ; Saad, S.T.O. ; Frenette, P.S. ; Brockschnieder, D. ; Costa, F.F. ; Stasch, J.P. ; Sandner, P. ; Conran, N.
  • Assuntos: Drug Discovery and Translational Medicine
  • É parte de: The Journal of pharmacology and experimental therapeutics, 2020-09, Vol.374 (3), p.469-478
  • Notas: ObjectType-Article-1
    SourceType-Scholarly Journals-1
    ObjectType-Feature-2
    content type line 23
    W.A.F. and H.C. contributed equally to this work as first authors.
  • Descrição: The complex pathophysiology of sickle cell anemia (SCA) involves intravascular hemolytic processes and recurrent vaso-occlusion, driven by chronic vascular inflammation, which result in the disease’s severe clinical complications, including recurrent painful vaso-occlusive episodes. Hydroxyurea, the only drug frequently used for SCA therapy, is a cytostatic agent, although it appears to exert nitric oxide/soluble guanylyl cyclase (sGC) modulating activity. As new drugs that can complement or replace the use of hydroxyurea are sought to further reduce vaso-occlusive episode frequency in SCA, we investigated the effects of the sGC agonists BAY 60-2770 (sGC activator) and BAY 41-2272 (sGC stimulator) in the presence or absence of hydroxyurea on SCA vaso-occlusive mechanisms and cell recruitment both ex vivo and in vivo. These agents significantly reduced stimulated human SCA neutrophil adhesive properties ex vivo in association with the inhibition of surface β 2-integrin activation. A single administration of BAY 60-2770 or BAY 41-2272 decreased tumor necrosis factor cytokine–induced leukocyte recruitment in a mouse model of SCA vaso-occlusion. Importantly, the in vivo actions of both agonists were significantly potentiated by the coadministration of hydroxyurea. Erythroid cell fetal hemoglobin (HbF) elevation is also a major goal for SCA therapy. BAY 41-2272 but not BAY 60-2770 at the concentrations employed significantly induced γ -globin gene transcription in association with HbF production in cultured erythroleukemic cells. In conclusion, sGC agonist drugs could represent a promising approach as therapy for SCA, for use either as stand-alone treatments or in combination with hydroxyurea.
  • Editor: Bethesda, MD: The American Society for Pharmacology and Experimental Therapeutics
  • Idioma: Inglês
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