@article{a70d99be0ec34af58353519e7737d8d6,
title = "Beneficial effects of soluble guanylyl cyclase stimulation and activation in sickle cell disease are amplified by hydroxyurea: In vitro and in vivo studies",
abstract = "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{\textquoteright}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 b2-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 g-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.",
author = "Ferreira, {W. A.} and H. Chweih and C. Lanaro and Almeida, {C. B.} and Brito, {P. L.} and Gotardo, {E. M.F.} and L. Torres and Miguel, {L. I.} and Franco-Penteado, {C. F.} and Leonardo, {F. C.} and F. Garcia and Saad, {S. T.O.} and Frenette, {P. S.} and D. Brockschnieder and Costa, {F. F.} and Stasch, {J. P.} and P. Sandner and N. Conran",
note = "Funding Information: W.A.F. received a postdoctoral fellowship from Bayer AG Pharmaceuticals. N.C. received grant funding from Bayer AG Pharmaceuticals through a restricted research grant. P.S.F. serves as consultant for Pfizer, has received research funding from Ironwood Pharmaceuticals, and is a shareholder of Cygnal Therapeutics. J.P.S. is senior advisor of Bayer AG. D.B. and P.S. are full-time employees of Bayer AG Pharmaceuticals. 1W.A.F. and H.C. contributed equally to this work as first authors. https://doi.org/10.1124/jpet.119.264606. s This article has supplemental material available at jpet.aspetjournals.org. Funding Information: The authors would like to thank the Instituto de Pesquisas Energ?ticas Nucleares (IPEN), S?o Paulo, for support with animal procedures. Funding Information: This work was funded by Bayer AG Pharmaceuticals, Germany. W.A.F. received a postdoctoral fellowship grant from Bayer Pharma AG. H.C., F.G., L.T., E.M.F.G., P.L.B., and L.I.M. are recipients of fellowships from Funda{\c c}{\~a}o de Amparo {\`a} Pesquisa do Estado de S. Paulo and Coordena{\c c}{\~a}o de Aperfei{\c c}oamento de Pessoal de N{\'i}vel Superior, Brazil. This work was supported by National Institutes of Health National Heart, Lung, and Blood Institute [Grant R01-HL069438] (to P.S.F.) and National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01-DK056638, Grant R01-DK116312, and Grant R01-DK112976] (to P.S.F). Publisher Copyright: Copyright {\textcopyright} 2020 The Author(s).",
year = "2020",
month = sep,
doi = "10.1124/JPET.119.264606",
language = "English (US)",
volume = "374",
pages = "469--478",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "3",
}