title: High red blood cell nitric oxide synthase activation is not associated with improved vascular function and red blood cell deformability in sickle cell anaemia.
abstract: Human red blood cells (RBC) express an active and functional endothelial-like nitric oxide (NO) synthase (RBC-NOS). We report studies on RBC-NOS activity in sickle cell anaemia (SCA), a genetic disease characterized by decreased RBC deformability and vascular dysfunction. Total RBC-NOS content was not significantly different in SCA patients compared to healthy controls; however, using phosphorylated RBC-NOS-Ser(1177) as a marker, RBC-NOS activation was higher in SCA patients as a consequence of the greater activation of Akt (phosphorylated Akt-Ser(473) ). The higher RBC-NOS activation in SCA led to higher levels of S-nitrosylated α- and β-spectrins, and greater RBC nitrite and nitrotyrosine levels compared to healthy controls. Plasma nitrite content was not different between the two groups. Laser Doppler flowmetric experiments demonstrated blunted microcirculatory NO-dependent response under hyperthermia in SCA patients. RBC deformability, measured by ektacytometry, was reduced in SCA in contrast to healthy individuals, and pre-shearing RBC in vitro did not improve deformability despite an increase of RBC-NOS activation. RBC-NOS activation is high in freshly drawn blood from SCA patients, resulting in high amounts of NO produced by RBC. However, this does not result in improved RBC deformability and vascular function: higher RBC-NO is not sufficient to counterbalance the enhanced oxidative stress in SCA.
authors.affiliation: Institute of Cardiovascular Research and Sport Medicine, Department of Molecular and Cellular Sport Medicine, German Sport University Cologne, Cologne, Germany; The German Research Centre of Elite Sport, German Sport University Cologne, Cologne, Germany.
authors.forename: Marijke
authors.initials: M
authors.lastname: Grau
authors.forename: Anaïs
authors.initials: A
authors.lastname: Mozar
authors.forename: Keyne
authors.initials: K
authors.lastname: Charlot
authors.forename: Yann
authors.initials: Y
authors.lastname: Lamarre
authors.forename: Linda
authors.initials: L
authors.lastname: Weyel
authors.forename: Frank
authors.initials: F
authors.lastname: Suhr
authors.forename: Bianca
authors.initials: B
authors.lastname: Collins
authors.forename: Stéphane
authors.initials: S
authors.lastname: Jumet
authors.forename: Marie-Dominique
authors.initials: MD
authors.lastname: Hardy-Dessources
authors.forename: Marc
authors.initials: M
authors.lastname: Romana
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lemonne
authors.forename: Maryse
authors.initials: M
authors.lastname: Etienne-Julan
authors.forename: Sophie
authors.initials: S
authors.lastname: Antoine-Jonville
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Bloch
authors.forename: Philippe
authors.initials: P
authors.lastname: Connes
mesh_terms: D000755:Anemia, Sickle Cell / Q000201:enzymology* / Q000473:pathology; D004789:Enzyme Activation; D004907:Erythrocyte Deformability; D004912:Erythrocytes / Q000201:enzymology* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013049:Spectrin / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D013049:Spectrin; C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D051057:Proto-Oncogene Proteins c-akt
keywords: blood rheology; microcirculation; nitric oxide synthase; sickle cell anaemia