Hydroxyurea up-Regulates Voltage-Dependent Anion Channels in Human Sickle Cell Erythrocytes.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2119-2119
Author(s):  
Nick Park ◽  
Daniel Diaz ◽  
Peggy Nakagawa ◽  
Geetha Puthenveetil ◽  
Paul Gershon ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Cell Survival ◽  
Outer Membrane ◽  
Sickle Cell ◽  
Conflicts Of Interest ◽  
Mitochondrial Outer Membrane ◽  
Red Cell ◽  
Anion Channels ◽  
Voltage Dependent ◽  
Red Cell Survival

Abstract Abstract 2119 Background: Hydroxyurea (HU) is clinically effective in reducing the frequency of pain crises in adults and children with sickle cell disease (SCD). In addition to increased fetal hemoglobin production, HU is known to induce macrocytosis in sickle cell erythrocytes and prolong red cell survival. However, the precise mechanism by which HU produces its varied effects is unknown. Isoelectric focusing has been applied to characterize changes in the red cell membrane following exposure to HU, but this technique has limitations in its ability to identify differences in specific membrane proteins. Mass spectrometry (MS) provides another proteomic approach in analyzing red cell proteins in SCD. Methods: Red blood cells were obtained from patients with SCD on HU therapy. After multiple wash and lysis steps, ghost membranes were obtained following ultracentrifugation. The membrane samples were then analyzed via tandem mass spectrometry and western immunoblot assay. Results: In comparison to a normal control, patients with SCD on HU therapy were found to have significantly elevated levels of voltage-dependent anion channels (VDAC) by MS, using a false discovery rate of less than five percent. The application of a stringent threshold initially identified 346 protein candidates. Out of these 346 proteins, 125 contained multiple peptides which all passed quantitation data filters according to quality parameters. Within the set of 125 proteins, 4 proteins were significantly up-regulated (up to 50-fold) in patients with SCD on HU therapy. VDAC2 and VDAC3 are members of the eukaryotic mitochondrial porin family which form channels through the mitochondrial outer membrane allowing diffusion of small hydrophilic molecules. VDAC1 can be found in both the mitochondrial outer membrane and the plasma membrane, where it is involved in cell volume regulation and apoptosis. Conclusions: Up-regulation of VDAC proteins may play an important role in altering the intracellular osmotic composition of the sickle cell erythrocyte resulting in decreased sickling and improved red cell survival in patients with SCD on HU therapy. Disclosures: No relevant conflicts of interest to declare.

Splenomegaly with Hypersplenism in Sickle Cell Anemia Treated by Radiation—Case Report

PEDIATRICS ◽  
1971 ◽  
Vol 48 (3) ◽  
pp. 457-458
Author(s):  
Annemarie Sommer ◽  
Stella B. Kontras
Keyword(s):  
Cell Survival ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Marked Improvement ◽  
Costal Margin ◽  
Red Cell ◽  
Older Children ◽  
Before And After ◽  
Red Cell Survival ◽  
Survival Studies

The incidence of splenomegaly in sickle cell anemia (defined as a spleen easily palpated below the costal margin in quiet respiration) appears to be around 10% after 10 years of age. Persistent splenomegaly in older children is rare and frequently is associated with hypersplenism. Splenectomy has been the treatment of choice in several reported cases based on red cell survival studies before and after splenectomy.1-3 Removal of the spleen has been found to be associated with marked improvement of previously very shortened red cell survival. We want to report the case of a 12-year-old boy with sickle cell anemia, splenomegaly, and sickle cell heart disease who was treated by radiation therapy for his enlarged spleen because of hypersplenism.

scholarly journals Arabidopsis Voltage-Dependent Anion Channels (VDACs): Overlapping and Specific Functions in Mitochondria

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 1023 ◽  
Author(s):  
Mickaële Hemono ◽  
Élodie Ubrig ◽  
Kevin Azeredo ◽  
Thalia Salinas-Giegé ◽  
Laurence Drouard ◽  
...  
Keyword(s):  
Stress Response ◽  
Outer Membrane ◽  
Mitochondrial Outer Membrane ◽  
Anion Channels ◽  
Essential Components ◽  
New Knowledge ◽  
Trna Import ◽  
Voltage Dependent ◽  
Mutant Lines ◽  
Mrna Isoform

Voltage-dependent anion channels (VDACs) are essential components of the mitochondrial outer membrane. VDACs are involved in the exchange of numerous ions and molecules, from ATP to larger molecules such as tRNAs, and are supposed to adjust exchanges in response to cell signals and stresses. Four major VDACs have been identified in Arabidopsis thaliana. The goal of this study was to explore the specific functions of these proteins, in particular, in tRNA import into mitochondria and stress response. The main results were: (i) VDACs appeared to differentially interact with tRNAs, and VDAC4 could be the major tRNA channel on the outer membrane, (ii) a VDAC3 mRNA isoform was found induced by different stresses, suggesting that VDAC3 might be specifically involved in early steps of stress response and (iii) an analysis of vdac3 and vdac1 mutant lines showed that VDAC3 and VDAC1 shared some, but not all functions. In conclusion, this work brings new knowledge on VDACs, which do not appear as interchangeable pores of the outer membrane and each VDAC has its own specificity.

scholarly journals Reticulocyte Survival in Sickle Cell Anemia: Effect of Cyanate

Blood ◽  
1972 ◽  
Vol 40 (5) ◽  
pp. 733-739 ◽  
Author(s):  
Blanche P. Alter ◽  
Yuet Wai Kan ◽  
David G. Nathan
Keyword(s):  
Cell Survival ◽  
Sickle Cell ◽  
Fetal Hemoglobin ◽  
Red Cells ◽  
Red Cell ◽  
Hemoglobin Molecule ◽  
Red Cell Survival ◽  
And Control

Abstract Cyanate prevents sickling in vitro and apparently prolongs the survival of 51Cr-tagged sickle erythrocytes in vivo. Cautious interpretation is required because the effects of cyanate on 51Cr binding to sickle and fetal hemoglobin-containing red cells are unknown, and comparison of the effect of cyanate on sickle red cell survival to control red cell survival must be performed sequentially. We have studied the survival of sickle reticulocytes utilizing radioactive amino acids that are incorporated into hemoglobin. Two informed adult patients with sickle cell disease were studied. In each study, two 50-ml samples of blood were incubated separately with 14C- and 3H-leucine for 2 hr, after which 50 mM cyanate was added to one aliquot for 1 hr. The cells were then washed and reinfused. Frequent venous samples were obtained, and the specific activities of 14C and 3H in the hemoglobin were followed. The t ½ of the carbamylated cells was tripled, but remained below normal. This method provides a generally useful measurement of the influence of drugs bound to red cells on reticulocyte lifespan. The labels are incorporated into the hemoglobin molecule of the reticulocyte, and simultaneous comparison of the survivals of the same cohort of drug-treated and control cells is achieved.

The effect of oral urea administration on red cell survival in sickle cell disease

1972 ◽  
Vol 264 (4) ◽  
pp. 283-287 ◽  
Author(s):  
THOMAS A. BENSINGER ◽  
LAVIZA MAHMOOD ◽  
MARCEL E. CONRAD ◽  
PAUL R. McCURDY
Keyword(s):  
Sickle Cell Disease ◽  
Cell Survival ◽  
Sickle Cell ◽  
Red Cell ◽  
Cell Disease ◽  
Red Cell Survival

scholarly journals The effect of carbon monoxide on red cell life span in sickle cell disease

Blood ◽  
1975 ◽  
Vol 46 (2) ◽  
pp. 253-259 ◽  
Author(s):  
E Beutler
Keyword(s):  
Carbon Monoxide ◽  
Sickle Cell Disease ◽  
Cell Survival ◽  
Sickle Cell ◽  
Red Cell ◽  
Cell Disease ◽  
Significant Prolongation ◽  
Cell Life ◽  
Red Cell Survival

Abstract Carbon monoxide at a concentration of 1000–2000 ppm was administered to sickle cell disease patients. In each of two patients, one 51Cr red cell survival study was carried out before CO administration, and a second study was initiated a few days before CO administration was started. In both, significant prolongation of red cell survival was observed, suggesting that the rheologic properties of sickle cells were favorably influenced in vivo. The administration of carbon monoxide is not recommended as a treatment for sickle cell disease. However, further trials would seem to be justified if conducted under carefully controlled conditions.

scholarly journals Ineffective Erythropoiesis Is the Major Cause of Microcytic Anemia in the TSAP6/Steap3 Null Mouse Model

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1332-1332
Author(s):  
Lionel Blanc ◽  
Julien Papoin ◽  
Michel Vidal ◽  
Robert Amson ◽  
Adam Telerman ◽  
...  
Keyword(s):  
Cell Survival ◽  
Mechanical Stability ◽  
Conflicts Of Interest ◽  
Microcytic Anemia ◽  
Red Cells ◽  
Null Mouse ◽  
Red Cell ◽  
Hemoglobin Content ◽  
Ineffective Erythropoiesis ◽  
Red Cell Survival

Abstract STEAP3 (Six-Transmembrane Epithelial Antigen of Prostate 3) is the major ferrireductase in the erythroblast. Also named TSAP6 (Tumor Supressor Activated Pathway 6) after it had been found to play a role in cancer, its total ablation in the mouse leads to severe microcytic and hypochromic red cells with moderate anemia. The protein function appears conserved among mammals, as patients carrying a nonsense mutation in the TSAP6/STEAP3 gene have been reported with hypochromic anemia. Here, we investigated the mechanism leading to the anemia. In the present study, using the TSAP6/Steap3 knockout mice, we undertook a comprehensive hematologic characterization of the red cell compartment. Red cell indices derived using ADVIA 120 blood counter confirmed the hypochromic microcytic anemia phenotype with a marked reduction in the mean corpuscular volume (MCV; 21.5fL ± 1.3fL in knockout vs 45.2fL ± 1.5fL in wild-type X ± SD, p<0.001) and mean cell hemoglobin content (MCH; 5.8pg ± 0.1pg vs 14.5pg ± 0.1pg, p<0.001). The reticulocyte count was marginally elevated (5.7% ± 1.2% vs 2.6% ± 0.4%, p<0.05) indicating that the anemia is proliferative. By phase contrast microscopy and transmission electron microscopy, we observed marked anisocytosis as well as the presence of fragmenting erythrocytes. Consistent with this observation, we found by ektacytometry decreased membrane mechanical stability of knockout red cells. Interestingly, we were unable to document significant changes in the expression levels of the major skeletal and transmembrane proteins to account for this decrease in the membrane stability. As defects in either the production or destruction of red cells can lead to anemia, we measured red cell survival and erythropoiesis in these mice. No differences in red cell survival could be documented using biotin labeled red cells implying that decreased survival cannot account for the anemia. However, when we monitored erythropoiesis using Ter119, CD44 and Forward Scatter (FSC) as markers of terminal differentiation, we found a decreased number of proerythroblasts in the bone marrow of TSAP6/Steap3-/- animals (2.20% ± 0.49% vs 4.07% ± 0.77%, p<0.01). In addition, progression from the proerythroblastic to the orthochromatic stage was also affected, with accumulation of cells at the polychromatic stage. These findings imply that ineffective erythropoiesis is the dominant cause of anemia in these mice and that TSAP6/Steap3 may play a role during erythropoiesis beyond its role as ferrireductase. It is interesting to note that while the phenotype of microcytic red cells with decreased hemoglobin content in the TSAP6/Steap3 null mouse is similar to red cells in thalassemic and porphyria mice, there are distinct differences in the etiology of the hematologic phenotype. Disclosures No relevant conflicts of interest to declare.

Role of voltage-dependent anion channels of the mitochondrial outer membrane in regulation of cell metabolism

BIOPHYSICS ◽  
2010 ◽  
Vol 55 (5) ◽  
pp. 733-739
Author(s):  
E. L. Holmuhamedov ◽  
C. Czerny ◽  
G. Lovelace ◽  
C. C. Beeson ◽  
T. Baker ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Cell Metabolism ◽  
Mitochondrial Outer Membrane ◽  
Anion Channels ◽  
Voltage Dependent

scholarly journals Red cell life span in sickle cell-hemoglobin C disease with a note about sickle cell-hemoglobin O ARAB

Blood ◽  
1975 ◽  
Vol 45 (2) ◽  
pp. 273-279 ◽  
Author(s):  
PR McCurdy ◽  
L Mahmood ◽  
AS Sherman
Keyword(s):  
Cell Survival ◽  
Sickle Cell ◽  
Red Cells ◽  
Red Cell ◽  
Relative Ease ◽  
Hemoglobin C ◽  
Cell Life ◽  
Red Cell Survival ◽  
Beta 2 ◽  
The One

Red cell survival was measured in ten subjects with S-C disease and one with S-O Arab (alpha 2 beta 2–121 glu yields lys) disease using both DF32p and 51Cr as tags. Red cell volume was slightly reduced in most patients (87% plus or minus 20% of predicted normal). In nine SC patients, mean red cell life (DF32p) was 28.9 plus or minus 4.0 days. For one SC subject it was significantly longer (47.9 days), as it was for the one with S-O Arab. The S-O Arab subject had irreversibly sickled cells in the peripheral blood, shereas those with SC had few (less than 1/1000 red cells) or none. The S-O Arab hemolysate gelled at a hemmoglobin concentration (16.2 g/100ml) near that for sickle cell anemia hemolysates (15.9 plus or minus 1.0 g/100 ml; n equals 8) but significantly lower than that for SC hemolysates (21.6 plus or minus 1.9 g/100 ml; n equals 5). It seems likely that properties of S-C red cells other than their relative ease of sickling contribute significantly to their rate of hemolysis.

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