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Hydroxyurea therapy modulates sickle cell anemia red blood cell physiology: Impact on RBC deformability, oxidative stress, nitrite levels and nitric oxide synthase signalling pathway

Elie Nader 1 Marijke Grau Romain Fort 1, 2 Bianca Collins Giovanna Cannas 3 Alexandra Gauthier 1 Katja Walpurgis Cyril Martin 1, 2 Wilhelm Bloch Solène Poutrel Arnaud Hot 4 Céline Renoux 1 Mario Thevis 5 Philippe Joly Marc Romana 6 Nicolas Guillot 7 Philippe Connes 1
1 LIBM - Laboratoire Interuniversitaire de Biologie de la Motricité
2 Labex Gr-Ex - Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge
3 Hôpital Edouard Herriot [CHU - HCL]
4 Service de Médecine Interne
5 Center for Preventive Doping Research
6 Pharmacogénétique et abords thérapeutiques des maladies héréditaires
7 CarMeN - Cardiovasculaire, métabolisme, diabétologie et nutrition
Abstract : Hydroxyurea (HU) has been suggested to act as a nitric oxide (NO) donor in sickle cell anemia (SCA). However, little is known about the HU NO-related effects on red blood cell (RBC) physiology and NO signalling pathway. Thirty-four patients with SCA (22 under HU treatment (HU+) and 12 without (HU-)) and 17 healthy subjects (AA) were included. RBC nitrite content, deformability and reactive oxygen species (ROS) levels were measured. RBC NO-synthase (RBC-NOS) signalling pathway was assessed by the measurement of RBC-NOS serine 1177 and RBC-AKT serine 473 phosphorylation. We also investigated the in vitro effects of Sodium Nitroprusside (SNP), a NO donor, on the same parameters in SCA RBC. RBC nitrite content was higher in HU+ than in HU-and AA. RBC deformability was decreased in SCA patients compared to AA but the decrease was more pronounced in HU-. RBC ROS level was increased in SCA compared to AA but the level was higher in HU-than in HU+. RBC-NOS serine 1177 and RBC-AKT serine 473 phosphorylation were decreased in HU+ compared to HU-and AA. SCA RBC treated with SNP showed increased deformability, reduced ROS content and a decrease in AKT and RBC-NOS phosphorylation. Our study suggests that HU, through its effects on foetal hemoglobin and possibly on NO delivery, would modulate RBC NO signalling pathway, RBC rheology and oxidative stress.
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https://hal.univ-antilles.fr/hal-01968408
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Submitted on : Monday, January 14, 2019 - 5:25:51 PM
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Elie Nader, Marijke Grau, Romain Fort, Bianca Collins, Giovanna Cannas, et al.. Hydroxyurea therapy modulates sickle cell anemia red blood cell physiology: Impact on RBC deformability, oxidative stress, nitrite levels and nitric oxide synthase signalling pathway. Nitric Oxide: Biology and Chemistry, Elsevier, 2018, 81, pp.28-35. ⟨10.1016/j.niox.2018.10.003⟩. ⟨hal-01968408⟩

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