High red blood cell nitric oxide synthase activation is not associated with improved vascular function and red blood cell deformability in sickle cell anaemia

Grau, Marijke; Mozar, Anaïs; Charlot, Keyne; Lamarre, Yann; Weyel, Linda; Suhr, Frank; Collins, Bianca; Jumet, Stéphane; Hardy‐Dessources, Marie‐Dominique; Romana, Marc; Lemonne, Nathalie; Etienne‐Julan, Maryse; Antoine‐Jonville, Sophie; Bloch, Wilhelm; Connes, Philippe

doi:10.1111/bjh.13185

Cited by 36 publications

(27 citation statements)

References 45 publications

(65 reference statements)

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“…Additionally, the demonstrated increase in uremic RBC-NOS activation proved similar to that found in erythrocytes from patients with sickle cell anemia [25], there being significant increased RBC-NOS activity, though the enzyme expression was slightly lower than in healthy subjects.…”

Section: Discussionsupporting

confidence: 75%

“…As mentioned above, in our study, we found that basal RBC-NOS was significantly more activated in uremic erythrocytes than in controls. There are indeed studies indicating that, under several pathological conditions, certain mechanisms that compensate deficient NO production may be activated [25,28,45]. In particular, these mechanisms include plasma oxidative stress, a condition existing in uremia [46,47], which can cause a paradoxical increase in RBC-NOS activity [48].…”

Section: Discussionmentioning

confidence: 99%

“…However, along with the study just mentioned, there are only a few studies concerning NO production, RBC-NOS expression, and activation in RBCs from other pathological conditions [23][24][25]. Some of them show an increased RBC-NOS activation in RBCs from sickle cell anemia patients and a significant increase in cGMP levels within RBCs has also been found as compared to healthy subjects [25,26]. Recently, it was shown that NO production was higher in RBCs from patients with type 2 diabetes than in controls [27].…”

Section: Introductionmentioning

confidence: 99%

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Nitric oxide synthetic pathway and cGMP levels are altered in red blood cells from end-stage renal disease patients

et al. 2016

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Red blood cells (RBCs) enzymatically produce nitric oxide (NO) by a functional RBC-nitric oxide synthase (RBC-NOS). NO is a vascular key regulatory molecule. In RBCs its generation is complex and influenced by several factors, including insulin, acetylcholine, and calcium. NO availability is reduced in end-stage renal disease (ESRD) and associated with endothelial dysfunction. We previously demonstrated that, through increased phosphatidylserine membrane exposure, ESRD-RBCs augmented their adhesion to human cultured endothelium, in which NO bioavailability decreased. Since RBC-NOS-dependent NO production in ESRD is unknown, this study aimed to investigate RBC-NOS levels/activation, NO production/bioavailability in RBCs from healthy control subjects (C, N = 18) and ESRD patients (N = 27). Although RBC-NOS expression was lower in ESRDRBCs, NO, cyclic guanosine monophosphate (cGMP), RBC-NOS Serine1177 phosphorylation level and eNOS/ Calmodulin (CaM)/Heat Shock Protein-90 (HSP90) interaction levels were higher in ESRD-RBCs, indicating increased enzyme activation. Conversely, following RBCs stimulation with insulin or ionomycin, NO and cGMP levels were significantly lower in ESRD-than in C-RBCs, suggesting that uremia might reduce the RBC-NOS response to further stimuli. Additionally, the activity of multidrug-resistance-associated protein-4 (MRP4; cGMPmembrane transporter) was significantly lower in ESRDRBCs, suggesting a possible compromised efflux of cGMP across the ESRD-RBCs membrane. This study for the first time showed highest basal RBC-NOS activation in ESRDRBCs, possibly to reduce the negative impact of decreased NOS expression. It is further conceivable that high NO production only partially affects cell function of ESRDRBCs maybe because in vivo they are unable to respond to physiologic stimuli, such as calcium and/or insulin.Keywords End-stage renal disease Á Red blood cells Á Nitric oxide Á cGMP Á Nitric oxide synthase Mario Bonomini, and Assunta Pandolfi have contributed equally to the study.Electronic supplementary material The online version of this article

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nitric oxide synthetic pathway and cGMP levels are altered in red blood cells from end-stage renal disease patients

et al. 2016

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“…Grau et al [99] demonstrated that stimulating the RBC NOS by the PI3 kinase/Akt pathway resulted in a greater amount of RBC nitrite and an improvement in RBC deformability in healthy subjects. Grau et al [100] and Mozar et al [101] recently focused on the RBC-NOS in SCA and SC patients, respectively: surprisingly, they found higher activity in comparison with healthy individuals, which resulted in a high amount of RBC nitrite and S-nitrosylated α- and β-spectrins. However, in contrast to what happened in healthy RBCs [99], the accumulation of NO into the RBCs of SCA patients was not associated with an improvement of RBC deformability [100].…”

Section: Modulators Of Blood Rheology In Scdmentioning

confidence: 99%

The role of blood rheology in sickle cell disease

et al. 2016

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Studies performed in the last decades have highlighted the need to better understand the contribution of the endothelium, vascular function, oxidative stress, inflammation, coagulation, hemolysis and vascular adhesion mechanisms to the pathophysiology of acute vaso-occlusive like events and chronic organ damages in sickle cell disease (SCD). Although SCD is a hemorheological disease, a few works focused on the contribution of blood viscosity, plasma viscosity, red blood cell deformability and aggregation in the pathophysiology of SCD. After a brief description of basic hemorheology, the present review focuses on the role of the hemorheological abnormalities in the causation of several SCD complications, mainly in sickle cell anemia and hemoglobin (Hb) SC disease. Several genetic and cellular modulators of blood rheology in SCD are discussed, as well as unresolved questions and perspectives.

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“…As NO is a key factor in SCD-associated endothelial dysfunction, it is not surprising that NO bioavailability is a major determinant of disease severity and of the frequency of vaso-occlusive events in SCD [41]. Furthermore, recent work reported abnormal endothelial function despite increased nitric oxide synthase levels and activation in red blood cells of SCD patients [42,43].…”

Section: Nitric Oxide Bioavailabilitymentioning

confidence: 99%