Impaired pentose phosphate shunt function in sickle cell disease: A potential mechanism for increased heinz body formation and membrane lipid peroxidation

1983 ◽  
Vol 15 (1) ◽  
pp. 1-13 ◽  
Author(s):  
Neil A. Lachant ◽  
Warren D. Davidson ◽  
Kouichi R. Tanaka
Keyword(s):  
Lipid Peroxidation ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Membrane Lipid ◽  
Pentose Phosphate ◽  
Membrane Lipid Peroxidation ◽  
Potential Mechanism ◽  
Cell Disease ◽  
Body Formation ◽  
Pentose Phosphate Shunt

scholarly journals A novel phospholipid in irreversibly sickled cells: evidence for in vivo peroxidative membrane damage in sickle cell disease

Blood ◽  
1984 ◽  
Vol 63 (2) ◽  
pp. 362-367 ◽  
Author(s):  
SK Jain ◽  
SB Shohet
Keyword(s):  
Lipid Peroxidation ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Membrane Damage ◽  
Membrane Lipid ◽  
Variable Number ◽  
Cell Disease ◽  
Sickle Cells ◽  
Peroxidative Damage

Abstract In individuals with sickle cell disease, a variable number of irreversibly sickled cells (ISC) is present that may contribute to the pathophysiology of sickle cell anemia. The present study was undertaken to determine the possible role of membrane lipid peroxidation in the genesis of ISC. After 24 hr of simple aerobic incubation, sickle cells accumulated 2–3 times more malonyldialdehyde (MDA), an end product of lipid peroxidation, than normal cells. To assess the possibility of peroxidative damage in ISC in vivo, ISC were separated from sickle blood using Stractan density gradients. Lipid extracts of the untreated ISC-enriched fraction of sickle blood showed significant fluorescence and contained a novel phospholipid:MDA adduct that was not seen in control cells. Taken together, these observations suggest that ISC have previously undergone lipid peroxidative damage and the accumulation of MDA in vivo.

scholarly journals A novel phospholipid in irreversibly sickled cells: evidence for in vivo peroxidative membrane damage in sickle cell disease

Blood ◽  
1984 ◽  
Vol 63 (2) ◽  
pp. 362-367 ◽  
Author(s):  
SK Jain ◽  
SB Shohet
Keyword(s):  
Lipid Peroxidation ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Membrane Damage ◽  
Membrane Lipid ◽  
Variable Number ◽  
Cell Disease ◽  
Sickle Cells ◽  
Peroxidative Damage

In individuals with sickle cell disease, a variable number of irreversibly sickled cells (ISC) is present that may contribute to the pathophysiology of sickle cell anemia. The present study was undertaken to determine the possible role of membrane lipid peroxidation in the genesis of ISC. After 24 hr of simple aerobic incubation, sickle cells accumulated 2–3 times more malonyldialdehyde (MDA), an end product of lipid peroxidation, than normal cells. To assess the possibility of peroxidative damage in ISC in vivo, ISC were separated from sickle blood using Stractan density gradients. Lipid extracts of the untreated ISC-enriched fraction of sickle blood showed significant fluorescence and contained a novel phospholipid:MDA adduct that was not seen in control cells. Taken together, these observations suggest that ISC have previously undergone lipid peroxidative damage and the accumulation of MDA in vivo.

scholarly journals Correlation of lipid peroxidation and nitric oxide metabolites, trace elements, and antioxidant enzymes in patients with sickle cell disease

2020 ◽  
Vol 34 (7) ◽  
Author(s):  
Charles Antwi‐Boasiako ◽  
Gifty Boatemaah Dankwah ◽  
Robert Aryee ◽  
Charles Hayfron‐Benjamin ◽  
George Aboagye ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Lipid Peroxidation ◽  
Trace Elements ◽  
Antioxidant Enzymes ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Disease ◽  
Nitric Oxide Metabolites

Mechanisms of vascular instability in a transgenic mouse model of sickle cell disease

2000 ◽  
Vol 279 (6) ◽  
pp. R1949-R1955 ◽  
Author(s):  
K. A. Nath ◽  
V. Shah ◽  
J. J. Haggard ◽  
A. J. Croatt ◽  
L. A. Smith ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Lipid Peroxidation ◽  
Sickle Cell Disease ◽  
Mouse Model ◽  
Systolic Blood Pressure ◽  
Transgenic Mouse ◽  
Sickle Cell ◽  
Transgenic Mouse Model ◽  
Cell Disease

We investigated a transgenic mouse model of sickle cell disease, homozygous for deletion of mouse β-globin and containing transgenes for human βSand βS-antillesglobins linked to the transgene for human α-globin. In these mice, basal cGMP production in aortic rings is increased, whereas relaxation to an endothelium-dependent vasodilator, A-23187, is impaired. In contrast, aortic expression of endothelial nitric oxide synthase (NOS) is unaltered in sickle mice, whereas expression of inducible NOS is not detected in either group; plasma nitrate/nitrite concentrations and NOS activity are similar in both groups. Increased cGMP may reflect the stimulatory effect of peroxides (an activator of guanylate cyclase), because lipid peroxidation is increased in aortae and in plasma in sickle mice. Despite increased vascular cGMP levels in sickle mice, conscious systolic blood pressure is comparable to that of aged-matched controls; sickle mice, however, evince a greater rise in systolic blood pressure in response to nitro-l-arginine methyl ester, an inhibitor of NOS. Systemic concentrations of the vasoconstrictive oxidative product 8-isoprostane are increased in sickle mice. We conclude that vascular responses are altered in this transgenic sickle mouse and are accompanied by increased lipid peroxidation and production of cGMP; we suggest that oxidant-inducible vasoconstrictor systems such as isoprostanes may oppose nitric oxide-dependent and nitric oxide-independent mechanisms of vasodilatation in this transgenic sickle mouse. Destabilization of the vasoactive balance in the sickle vasculature by clinically relevant states may predispose to vasoocclusive disease.

scholarly journals Comorbidity of Glucose-6-Phosphate Dehydrogenase Deficiency and Sickle Cell Disease Exert Significant Effect on RBC Indices

Anemia ◽  
2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Samuel Antwi-Baffour ◽  
Jonathan Kofi Adjei ◽  
Peter Owadee Forson ◽  
Stephen Akakpo ◽  
Ransford Kyeremeh ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Blood Cells ◽  
G6pd Deficiency ◽  
Pentose Phosphate ◽  
Full Blood Count ◽  
Cell Disease ◽  
Blood Disorder ◽  
Glucose 6 Phosphate Dehydrogenase

Background. Glucose-6-phosphate dehydrogenase (G6PD) converts glucose-6-phosphate into 6-phosphogluconate in the pentose phosphate pathway and protects red blood cells (RBCs) from oxidative damage. Their deficiency therefore makes RBCs prone to haemolysis. Sickle cell disease (SCD) on the other hand is a hereditary blood disorder in which there is a single nucleotide substitution in the codon for amino acid 6 substituting glutamic acid with valine. SCD patients are prone to haemolysis due to the shape of their red blood cells and if they are deficient in G6PD, the haemolysis may escalate. Reported studies have indicated variations in the prevalence of G6PD deficiency in SCD patients and as such further work is required. The aim of this study was therefore to estimate the incidence of G-6-PD deficiency among SCD patients and to determine its impact on their RBC parameters as a measure of incidence of anaemia.Methods. A total of 120 clinically diagnosed SCD patients of genotypes HbSS and HbSC were recruited into the study. About 5ml of blood was collected via venipuncture from each patient and used to run G6PD, full blood count, and haemoglobin (Hb) electrophoresis tests. The data were analyzed using SPSS version 20 and Graphpad prism.Result. G6PD deficiency was detected in 43 (35.83%) of the participants made up of 16 (13.33%) males and 27 (22.50%) females of whom 17 (14.17%) had partial deficiency and 10 (8.33%) full deficiency. Statiscally significant differences p=0.036 and p=0.038 were established between the Hb concentration of the participants having a G6PD deficiency and those with normal G6PD activity for males and females, respectively.Conclusion. From the results obtained, it implies that G6PD deficiency may increase the severity of anaemia in SCD patients. There is therefore the need to screen all SCD patients for G6PD deficiency to ensure that their condition is not exacerbated during treatment.

Excess heme upregulates heme oxygenase 1 and promotes cardiac ferroptosis in mice with sickle cell disease

Blood ◽  
2021 ◽  
Author(s):  
Archita Venugopal Menon ◽  
Jing Liu ◽  
Hanting Phoebe Tsai ◽  
Lingxue Zeng ◽  
Seungjeong Yang ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Sickle Cell Disease ◽  
Heme Oxygenase ◽  
Sickle Cell ◽  
Cardiovascular Complications ◽  
Heme Oxygenase 1 ◽  
Cell Disease ◽  
Cardiac Damage ◽  
Downstream Effects ◽  
Free Heme

Sickle cell disease (SCD) is characterized by increased hemolysis which results in plasma heme overload and ultimately cardiovascular complications. Here, we hypothesized that increased heme in SCD causes upregulation of heme oxygenase 1 (Hmox1) which consequently drives cardiomyopathy through ferroptosis, an iron-dependent non-apoptotic form of cell death. First, we demonstrated that the Townes SCD mice had higher levels of hemopexin-free heme in the serum and increased cardiomyopathy, which was corrected by hemopexin supplementation. Cardiomyopathy in SCD mice was associated with upregulation of cardiac Hmox1, and inhibition or induction of Hmox1 improved or worsened cardiac damage, respectively. Since free iron, a product of heme degradation through Hmox1, has been implicated in toxicities including ferroptosis, we evaluated the downstream effects of elevated heme in SCD. Consistent with Hmox1 upregulation and iron overload, levels of lipid peroxidation and ferroptotic markers increased in SCD mice, which were corrected by hemopexin administration. Moreover, ferroptosis inhibitors decreased cardiomyopathy, whereas a ferroptosis inducer erastin exacerbated cardiac damage in SCD and induced cardiac ferroptosis in non-sickling mice. Finally, inhibition or induction of Hmox1 decreased or increased cardiac ferroptosis in SCD mice, respectively. Together, our results identify ferroptosis as a key mechanism of cardiomyopathy in SCD.

scholarly journals Membrane Lipid Alterations in Hemoglobinopathies

Hematology ◽  
2007 ◽  
Vol 2007 (1) ◽  
pp. 68-73 ◽  
Author(s):  
Frans A. Kuypers
Keyword(s):  
Sickle Cell Disease ◽  
Lipid Bilayer ◽  
Sickle Cell ◽  
Complex Mixture ◽  
Membrane Lipid ◽  
Acute Chest Syndrome ◽  
Antioxidant Systems ◽  
Cell Disease ◽  
Rbc Membrane ◽  
Lipid Organization

Abstract The red blood cell (RBC) membrane is a complex mixture of lipids and proteins. Hundreds of phospholipid molecular species spontaneously arrange themselves in a lipid bilayer and move rapidly in the plane as well as across the bilayer in a dynamic but highly organized fashion. Areas enriched in certain lipids determine proper protein function. Phospholipids are asymmetrically distributed across the lipid bilayer with phosphatidylserine (PS) exclusively on the inside. Both the composition and organization of the RBC membrane is well maintained. Alterations lead to apoptosis during erythropoiesis or early demise of the cell in the circulation. The mechanisms that govern the maintenance of the lipid bilayer are only recently being unraveled at the individual protein level. Oxidized lipids are rapidly repaired using fatty acids taken up from plasma to maintain membrane integrity. Several isoforms of a RBC acyl-Coenzyme A (CoA) synthase have been reported, as well as the first member of a family of lysophospholipid acylCoA acyltransferases. Phospholipid asymmetry is maintained by the recently identified RBC amino-phospholipid translocase. These enzymes, essential in maintaining membrane lipid organization, are affected by oxidant stress or an increase in cytosolic calcium. Normal lipid composition and organization is lost in subpopulations of RBC in hemoglobinopathies such as sickle cell disease and thalassemia. Despite elaborate antioxidant systems, lipids and membrane proteins, including those that maintain lipid organization, are damaged in these cells. This in turn leads to improper repair of damaged RBC membranes and altered interactions of RBCs with other blood cells and plasma components that play a role in the pathology that defines these disorders. The altered lipid bilayer in RBCs in hemoglobinopathies leads to premature removal (anemia) and imbalance in hemostasis, and plays a role in vaso-occlusive crisis in sickle cell disease. Lipid breakdown products of PS-exposing cells result in vascular dysfunction, including acute chest syndrome in sickle cell disease. In summary, altered membrane lipids play an important role in the pathology of hemoglobinopathies and characterization of the proteins involved in lipid turnover will elucidate the pathways that maintain plasma membrane organization and cellular viability.

Increased Chromosomal Breaks in Sickle Cell Disease as Evidenced by the Presence of Micronuclei in Erythrocytes.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3807-3807
Author(s):  
Ashutosh Lal ◽  
Amrita Bhagat ◽  
Wafa Atamna ◽  
Tal Offer ◽  
Elliott P. Vichinsky ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Ischemia Reperfusion ◽  
Micronucleus Assay ◽  
Membrane Lipid ◽  
Cell Disease ◽  
Dna Breaks ◽  
Fluorescent Markers ◽  
Double Stranded Dna ◽  
Chromosomal Breaks

Abstract Double-stranded DNA breaks are serious lesions that contribute to the pathogenesis of cancer and chronic illnesses. Free radical injury is an important mechanism for the production of DNA modifications that eventually lead to chromosomal breaks. The generation of free radicals is increased in sickle cell disease (SCD) owing to the presence of the relatively unstable HbS and recurrent ischemia-reperfusion events. In the present study, a sensitive reticulocyte micronucleus assay was used to determine the frequency of chromosomal breaks in patients with SCD (Offer et al. FASEB J. 2005;19:485). A micronucleus is a piece of a chromosome left behind in a reticulocyte as a consequence of DNA double-stranded break after the nucleus is extruded. Blood samples were obtained from patients with SCD (n=33) and healthy volunteers (n=23). After immunomagnetic enrichment of CD71+ reticulocytes (Trf-Ret), RNA was removed with RNAse, and the cells were stained for miconuclei using the DNA dye 7-aminoactinomycin D (7-AAD) followed by flow cytometric evaluation. The appearance of reactive oxygen species in cytosol and membrane lipid oxidation in RBCs were measured by flow cytometry using the fluorescent markers 2, 7-dichlorofluorescin diacetate (DCF) and C11-BODIPY, respectively. The frequency of micronucleated Trf-Ret was significantly higher (p<.0001) in patients with SCD (mean 3.061/10,000 Trf-Ret, range 0.256 to 9.779) as compared with normal controls (mean 0.750/10,000 Trf-Ret, range 0.043 to 2.659). Mean DCF (125.1%) and C11-BODIPY (117.6%) fluorescence intensities were significantly greater than the mean control value (100%, p 0.0001). Our data indicate that patients with sickle cell disease have increased double stranded DNA-breaks compared with healthy controls, and suggest that elevated production of oxidants could contribute to the development of genetic damage in these patients.

scholarly journals Structural and Functional Insight of Sphingosine 1-Phosphate-Mediated Pathogenic Metabolic Reprogramming in Sickle Cell Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2474-2474
Author(s):  
Kaiqi Sun ◽  
Yang Xia ◽  
Angelo D'Alessandro ◽  
Mostafa H Ahmed ◽  
Yujin Zhang ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Hydrophobic Interactions ◽  
Pentose Phosphate ◽  
Metabolic Reprogramming ◽  
Aliphatic Chain ◽  
Oxygen Binding ◽  
Cell Disease ◽  
Sphingosine 1 Phosphate ◽  
Sticky Tape

Abstract Sphingosine 1-phosphate (S1P) is a bioactive signaling lipid highly enriched in mature erythrocytes. Previous study has revealed that levels of S1P are significantly elevated in patients and mice with Sickle Cell Disease (SCD), a devastating and highly prevalent genetic hemolytic disorder that causes life-threatening hemolysis, tissue damage, and organ dysfunction with very limited treatment. Moreover, the activity of S1P generating enzyme-Sphingosine Kinase 1 (SphK1) is increased in human and mouse SCD erythrocytes, and inhibition of SphK1 decreased erythrocyte sickling. However, the structural and functional basis for the pathogenic nature of S1P in SCD remains obscure. Here, we report that increased erythrocyte S1P promotes pathogenic metabolic reprogramming coupled to increased channeling of glucose to glycolysis rather than through the pentose phosphate pathway (PPP). Suppressed PPP causes compromised glutathione homeostasis and increased oxidative stress, while enhanced glycolysis induces production of 2,3-bisphosphoglycerate (2,3-BPG) and thus increasing deoxygenated sickle Hb (deoxyHbS), deoxyHbS polymerization, sickling, hemolysis and disease progression. S1P functioning intracellularly binds to deoxyHbS, facilitates deoxyHbS anchoring to the membrane, induces release of membrane-bound glycolytic enzymes and in turn switches glucose flux towards glycolysis relative to the PPP. Extending from SCD, we unexpectedly found that S1P and 2,3-BPG work synergistically to decrease both HbA and HbS oxygen binding affinity. The crystal structure of HbA complexed with S1P alone or in combination with 2,3-BPG at 1.9 Å resolution revealed the overall architecture and unique features of S1P-2,3-BPG-deoxyHbA complex. In the presence of 2,3-BPG, S1P binds to the surface of 2,3-BPG-deoxyHbA and causes additional conformation changes to the T-state Hb. Phosphate moiety of the surface bound S1P engages in a highly positive region close to a1-heme while its aliphatic chain snakes along a shallow cavity making hydrophobic interactions in the "switch region", as well as with b2-heme like a molecular "sticky tape" with the last 3-4 carbon atoms sticking out into bulk solvent. Altogether, our findings provide functional and structural bases underlying pathogenic consequences of elevated S1P in SCD and its potential role in normal erythrocyte physiology. Disclosures Kato: Mast Therapeutics: Consultancy; Bayer: Research Funding.

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