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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.
Nitric Oxide. 2018 12 01; 81:28-35.NO

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 serine1177 and RBC-AKT serine473 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 serine1177 and RBC-AKT serine473 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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Publisher Full Text (DOI)

Authors+Show Affiliations

Nader E
Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM) EA7424, Team « Vascular Biology and Red Blood Cell », Université Claude Bernard Lyon 1, Université de Lyon, France; Laboratoire d'Excellence du Globule Rouge (Labex GR-Ex), PRES Sorbonne, Paris, France.
Grau M
Molecular and Cellular Sport Medicine, Deutsche Sporthochschule Köln, Germany.
Fort R
Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM) EA7424, Team « Vascular Biology and Red Blood Cell », Université Claude Bernard Lyon 1, Université de Lyon, France; Laboratoire d'Excellence du Globule Rouge (Labex GR-Ex), PRES Sorbonne, Paris, France; Département de Médecine Interne, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France.
Collins B
Molecular and Cellular Sport Medicine, Deutsche Sporthochschule Köln, Germany.
Cannas G
Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM) EA7424, Team « Vascular Biology and Red Blood Cell », Université Claude Bernard Lyon 1, Université de Lyon, France; Laboratoire d'Excellence du Globule Rouge (Labex GR-Ex), PRES Sorbonne, Paris, France; Département de Médecine Interne, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France.
Gauthier A
Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM) EA7424, Team « Vascular Biology and Red Blood Cell », Université Claude Bernard Lyon 1, Université de Lyon, France; Laboratoire d'Excellence du Globule Rouge (Labex GR-Ex), PRES Sorbonne, Paris, France; Institut d'Hématologie et d'Oncologie Pédiatrique, Hospices Civils de Lyon, Lyon, France.
Walpurgis K
Center for Preventive Doping Research - Institute of Biochemistry, German Sport University Cologne, Am Sportpark Müngersdorf 6, 50933, Cologne, Germany.
Martin C
Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM) EA7424, Team « Vascular Biology and Red Blood Cell », Université Claude Bernard Lyon 1, Université de Lyon, France; Laboratoire d'Excellence du Globule Rouge (Labex GR-Ex), PRES Sorbonne, Paris, France.
Bloch W
Molecular and Cellular Sport Medicine, Deutsche Sporthochschule Köln, Germany.
Poutrel S
Département de Médecine Interne, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France.
Hot A
Département de Médecine Interne, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France.
Renoux C
Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM) EA7424, Team « Vascular Biology and Red Blood Cell », Université Claude Bernard Lyon 1, Université de Lyon, France; Laboratoire d'Excellence du Globule Rouge (Labex GR-Ex), PRES Sorbonne, Paris, France; Laboratoire de Biochimie et de Biologie Moléculaire, UF de biochimie des pathologies érythrocytaires, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Lyon, France.
Thevis M
Center for Preventive Doping Research - Institute of Biochemistry, German Sport University Cologne, Am Sportpark Müngersdorf 6, 50933, Cologne, Germany.
Joly P
Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM) EA7424, Team « Vascular Biology and Red Blood Cell », Université Claude Bernard Lyon 1, Université de Lyon, France; Laboratoire d'Excellence du Globule Rouge (Labex GR-Ex), PRES Sorbonne, Paris, France; Laboratoire de Biochimie et de Biologie Moléculaire, UF de biochimie des pathologies érythrocytaires, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Lyon, France.
Romana M
Laboratoire d'Excellence du Globule Rouge (Labex GR-Ex), PRES Sorbonne, Paris, France; UMR Inserm 1134, Hôpital Ricou, Centre Hospitalier Universitaire, Pointe-à-Pitre, Guadeloupe.
Guillot N
Laboratoire Carmen Inserm 1060, INSA Lyon, Université Claude Bernard Lyon 1, Université de Lyon, Villeurbanne, France.
Connes P
Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM) EA7424, Team « Vascular Biology and Red Blood Cell », Université Claude Bernard Lyon 1, Université de Lyon, France; Laboratoire d'Excellence du Globule Rouge (Labex GR-Ex), PRES Sorbonne, Paris, France; Institut Universitaire de France, Paris, France. Electronic address: pconnes@yahoo.fr.

MeSH

AdultAnemia, Sickle CellErythrocyte DeformabilityErythrocytesFemaleHumansHydroxyureaMaleNitric OxideNitric Oxide SynthaseNitritesNitroprussideOxidative StressPhosphorylationProto-Oncogene Proteins c-aktReactive Oxygen SpeciesSignal Transduction

Pub Type(s)

Controlled Clinical Trial
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30342855

Citation

Nader, Elie, 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, vol. 81, 2018, pp. 28-35.
Nader E, Grau M, Fort R, 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. 2018;81:28-35.
Nader, E., Grau, M., Fort, R., Collins, B., Cannas, G., Gauthier, A., Walpurgis, K., Martin, C., Bloch, W., Poutrel, S., Hot, A., Renoux, C., Thevis, M., Joly, P., Romana, M., Guillot, N., & Connes, P. (2018). 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, 81, 28-35. https://doi.org/10.1016/j.niox.2018.10.003
Nader E, 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. 2018 12 1;81:28-35. PubMed PMID: 30342855.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hydroxyurea therapy modulates sickle cell anemia red blood cell physiology: Impact on RBC deformability, oxidative stress, nitrite levels and nitric oxide synthase signalling pathway. AU - Nader,Elie, AU - Grau,Marijke, AU - Fort,Romain, AU - Collins,Bianca, AU - Cannas,Giovanna, AU - Gauthier,Alexandra, AU - Walpurgis,Katja, AU - Martin,Cyril, AU - Bloch,Wilhelm, AU - Poutrel,Solène, AU - Hot,Arnaud, AU - Renoux,Céline, AU - Thevis,Mario, AU - Joly,Philippe, AU - Romana,Marc, AU - Guillot,Nicolas, AU - Connes,Philippe, Y1 - 2018/10/19/ PY - 2018/07/11/received PY - 2018/10/16/revised PY - 2018/10/17/accepted PY - 2018/10/22/pubmed PY - 2019/2/23/medline PY - 2018/10/22/entrez KW - Deformability KW - Hydroxyurea KW - Nitric oxide KW - Oxidative stress KW - Sickle cell anaemia SP - 28 EP - 35 JF - Nitric oxide : biology and chemistry JO - Nitric Oxide VL - 81 N2 - 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 serine1177 and RBC-AKT serine473 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 serine1177 and RBC-AKT serine473 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. SN - 1089-8611 UR - https://www.unboundmedicine.com/medline/citation/30342855/Hydroxyurea_therapy_modulates_sickle_cell_anemia_red_blood_cell_physiology:_Impact_on_RBC_deformability_oxidative_stress_nitrite_levels_and_nitric_oxide_synthase_signalling_pathway_ DB - PRIME DP - Unbound Medicine ER -