Association Between Nitric Oxide, Oxidative Stress, Eryptosis, Red Blood Cell Microparticles, and Vascular Function in Sickle Cell Anemia

Abstract

Chronic hemolysis, enhanced oxidative stress, and decreased nitric oxide (NO) bioavailability promote vasculopathy in sickle cell anemia (SCA). Oxidative stress and NO are known to modulate eryptosis in healthy red blood cells (RBCs); however, their role in SCA eryptosis and their impact on the genesis of RBC-derived microparticles (RBC-MPs) remains poorly described. RBC-MPs could play a role in vascular dysfunction in SCA. The aims of this study were to evaluate the roles of oxidative stress and NO in eryptosis and RBC-MPs release, and to determine whether RBC-MPs could be involved in vascular dysfunction in SCA. Markers of eryptosis and oxidative stress, plasma RBC-MPs concentration and arterial stiffness were compared between SCA and healthy (AA) individuals . In-vitro experiments were performed to test: 1) the effects of oxidative stress (antioxidant: n-acetylcysteine (NAC); pro-oxidant: cumene hydroperoxide) and NO (NO donor: sodium nitroprusside (SNP); NO-synthase inhibitor (L-NIO)) on eryptosis, RBC deformability and RBC-MP genesis; 2) the effects of SCA/AA-RBC-MPs on human aortic endothelial cell (HAEC) inflammatory phenotype and TLR4 pathway. Eryptosis, RBC-MPs, oxidative stress and arterial stiffness were increased in SCA. NAC increased RBC deformability and decreased eryptosis and RBC-MPs release, while cumene did the opposite. SNP increased RBC deformability and limited eryptosis, but had no effect on RBC-MPs. L-NIO did not affect these parameters. Arterial stiffness was correlated with RBC-MPs concentration in SCA. RBC-MPs isolated directly from SCA blood increased adhesion molecules expression and the production of cytokines by HAEC compared to those isolated from AA blood. TLR4 inhibition alleviated these effects. Our data show that oxidative stress could promote eryptosis and the release of RBC-MPs that are potentially involved in macrovascular dysfunction in SCA.

Acute Cycling Exercise Induces Changes in Red Blood Cell Deformability and Membrane Lipid Remodeling

“…In this setting, accumulation of oxidative damage results in decreased deformability and generation of RBC-MPs. A recent study also demonstrated the key role of oxidative stress in RBC deformability and the release of RBC-MPs in the context of sickle cell anemia [ 26 ]. The application of omics technologies, including metabolomics, lipidomics, and proteomics, has contributed significantly to the understanding of RBC responses to oxidative stress [ 27 ].…”

Streptococcus pneumoniae and Its Virulence Factors H2O2 and Pneumolysin Are Potent Mediators of the Acute Chest Syndrome in Sickle Cell Disease

“…Vascular damage in ACS is at least partially mediated by generation of oxygen-related molecules, such as superoxide (O 2 − ), hydrogen peroxide (H 2 O 2 ), peroxynitrite (ONOO − ), and the hydroxyl (•OH) radical [ 5 ]. Enhanced intravascular hemolysis can lead to an accumulation of hemoglobin (Hb) and heme in plasma, which in turn decreases bioavailability of nitric oxide (NO) and enhances ROS generation [ 2 ]. Moreover, the continuous oxidation of the heme iron in Hb (auto-oxidation) and impaired anti-oxidant capacity promote a pro-oxidative environment in sickle erythrocytes, which compromises overall redox balance in these cells and affects their metabolic state.…”

“…Sickle cell disease (SCD) arises from homozygous single nucleotide polymorphisms (SNP) in the sixth codon of the β-globin gene (HbSS) on chromosome 11 which causes substitution of a single valine (Val) residue for glutamic acid (Glu) [ 1 ]. As a consequence, HbSS can polymerize under deoxygenation and mediates the sickling of erythrocytes [ 2 ].…”

The Redox Balance and Membrane Shedding in RBC Production, Maturation, and Senescence

“…Several findings favor the primary involvement of oxidative stress in vesiculation ( Szigyarto et al, 2018 ; Nader et al, 2020 ): (I) MVs are enriched in antioxidant enzymes and irreversibly oxidized Hb ( Sudnitsyna et al, 2020 ); (II) some studies have indicated that treatment with oxidants decreased vesiculation, whereas antioxidants have an opposite effect ( Stowell et al, 2013 ; Nader et al, 2020 ). Oxidative stress, through the effects of ROS, may trigger both mechanisms of vesiculation—the clustering of Band-3 and the accumulation of intracellular Ca 2+ .…”