Deoxygenation-induced and Ca2+ dependent phosphatidylserine externalisation in red blood cells from normal individuals and sickle cell patients

Weiss, Erwin; Cytlak, Urszula; Rees, David C.; Osei, A; Gibson, John S.

doi:10.1016/j.ceca.2011.10.005

Cited by 79 publications

(72 citation statements)

References 44 publications

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“…The rise in intracellular Ca 2+ , [Ca 2+ ], may also play a role in lipid scrambling. Previous findings are consistent with deoxygenation‐induced Ca 2+ entry, predominantly via P sickle , contributing to elevation of intracellular Ca 2+ levels and leading to increased PS exposure (Weiss et al , 2012; Cytlak et al , 2013). Low micromolar levels of Ca 2+ are required (Weiss et al , 2012; Cytlak et al , 2013), which although representing a higher Ca 2+ affinity for scrambling than hitherto thought, still represent relatively high levels, even for deoxygenated sickle cells (Etzion et al , 1993).…”

supporting

confidence: 74%

“…Under these conditions, because of the Donnan ratio, free intracellular [Ca 2+ ], [Ca 2+ ] i is about double that of free extracellular values (Flatman, 1980; Muzyamba et al , 2006). Previous experiments have shown that PS exposure in Ca 2+ permeabilised red cells occurs when free [Ca 2+ ] o is increased above about 0·1 μmol/l (Weiss et al , 2012; Cytlak et al , 2013). Similar findings were found in the present work with half maximal PS exposure observed at a free [Ca 2+ ] o of 0·34 ± 0·02 μmol/l ( n = 22).…”

Section: Resultsmentioning

confidence: 99%

“…By analogy to apoptosis in nucleated cells, the process of PS exposure in red cells and their subsequent removal from the circulation by macrophages, has been termed eryptosis (Lang et al , 2006). In SCA, a high, but variable proportion of red cells shows PS exposure (Tait & Gibson, 1994; Kuypers et al , 1996; de Jong et al , 2001; Weiss et al , 2012), which further increases upon deoxygenation, haemoglobin polymerisation and the sickling shape change (Lubin et al , 1981; Blumenfeld et al , 1991; Weiss et al , 2012; Cytlak et al , 2013). This red cell lipid scrambling may therefore participate in the pathogenesis of SCA, and contribute to both the chronic anaemia and the acute ischaemic episodes characteristic of the condition (Rees et al , 2010), and is thus central to the clinical progression of the disease.…”

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confidence: 99%

“…Elevation of intracellular Ca 2+ can elicit both these processes (Williamson et al , 1992; Basse et al , 1996; Woon et al , 1999; Haest, 2003; Bevers & Williamson, 2010). Flippase inhibition is generally considered to be more sensitive to Ca 2+ (Bitbol et al , 1987; Basse et al , 1996; Kamp et al , 2001; Bevers & Williamson, 2010) although more recent work suggests that, in fact, lipid scrambling is activated at similar Ca 2+ concentrations to flippase inhibition (Weiss et al , 2012; Cytlak et al , 2013). Nevertheless, our understanding of the conditions and mechanisms of PS exposure in red cells from SCA patients remains incomplete.…”

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Oxidative stress and phosphatidylserine exposure in red cells from patients with sickle cell anaemia

et al. 2018

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SummaryPhosphatidylserine (PS) exposure increases as red cells age, and is an important signal for the removal of senescent cells from the circulation. PS exposure is elevated in red cells from sickle cell anaemia (SCA) patients and is thought to enhance haemolysis and vaso‐occlusion. Although precise conditions leading to its externalisation are unclear, high intracellular Ca2+ has been implicated. Red cells from SCA patients are also exposed to an increased oxidative challenge, and we postulated that this stimulates PS exposure, through increased Ca2+ levels. We tested four different ways of generating oxidative stress: hypoxanthine and xanthine oxidase, phenazine methosulphate, nitrite and tert‐butyl hydroperoxide, together with thiol modification with N‐ethylmaleimide (NEM), dithiothreitol and hypochlorous acid (HOCl), in red cells permeabilised to Ca2+ using bromo‐A23187. Unexpectedly, our findings showed that the four oxidants significantly reduced Ca2+‐induced PS exposure (by 40–60%) with no appreciable effect on Ca2+ affinity. By contrast, NEM markedly increased PS exposure (by about 400%) and slightly but significantly increased the affinity for Ca2+. Dithiothreitol modestly reduced PS exposure (by 25%) and HOCl had no effect. These findings emphasise the importance of thiol modification for PS exposure in sickle cells but suggest that increased oxidant stress alone is not important.

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confidence: 74%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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Oxidative stress and phosphatidylserine exposure in red cells from patients with sickle cell anaemia

et al. 2018

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“…Eryptosis is elicited by a wide variety of xenobiotics [13,, including tannic acid [48], honokiol [62], gossypol [46], gambogic acid [63], tanshinone II A [47], apigenin [64], ursolic acid [65], thymoquinone [66], oridonin [67] and a-lipoic acid [14]. Moreover, eryptosis is accelerated in a wide variety of clinical conditions [11,68], including sepsis [69], fever [16], malaria [29,[70][71][72][73], sickle cell disease [43,[74][75][76][77][78][79][80], Wilson's disease [81], iron deficiency [82], malignancy [83], metabolic syndrome [44], diabetes [30], renal insufficiency [39,84,85], haemolytic uremic syndrome [86], hyperphosphataemia [87] and phosphate depletion [68].…”

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Stimulation of Suicidal Erythrocyte Death by Sulforaphane

Alzoubi

Calabrò

Faggio

et al. 2014

Basic Clin Pharma Tox

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Sulforaphane, an isothiocyanate from cruciferous vegetable, counteracts malignancy. The effect is at least in part due to the stimulation of suicidal death or apoptosis of tumour cells. Mechanisms invoked in sulforaphane-induced apoptosis include mitochondrial depolarization and altered gene expression. Despite the lack of mitochondria and nuclei, erythrocytes may, similar to apoptosis of nucleated cells, enter eryptosis, a suicidal cell death characterized by cell shrinkage and phosphatidylserine translocation to the erythrocyte surface. This study explored whether sulforaphane influences eryptosis. To this end, the effect of sulforaphane exposure on human erythrocyte [Ca 2+ ] i , cell volume and phosphatidylserine surface abundance was quantified by flow cytometry. Materials and MethodsErythrocytes, solutions and chemicals. Fresh Li-heparinanticoagulated blood samples were kindly provided by the blood bank of the University of T€ ubingen. The study was approved by the ethics committee of the University of T€ ubingen (184/2003 V). The blood was centrifuged at 125 9 g for 20 min. at 23°C, and the platelet-and leucocyte-containing supernatant was disposed. Erythrocytes were incubated in vitro at a haematocrit of 0.4% in Ringer solution containing (in mM) 125 NaCl, 5 KCl, 1 MgSO 4 , 32 N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid (HEPES), 5 glucose, 1 CaCl 2 ; pH 7.4 at 37°C for 48 hr. Where indicated, erythrocytes were exposed to sulforaphane (Sigma-Aldrich, Schnelldorf, Germany) at the indicated concentrations,

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Ca2+-dependent suicidal erythrocyte death following zearalenone exposure

Jilani

Läng

2013

Arch Toxicol

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Zearalenone, a cereal mycotoxin with mycoestrogen activity and effect on fertility, is known to trigger apoptosis of a variety of nucleated cell types including hematopoietic progenitor cells. In analogy to apoptosis of nucleated cells, eryptosis, the suicidal death of erythrocytes, leads to cell shrinkage and cell membrane scrambling with phosphatidylserine exposure at the erythrocyte surface. The most important stimulator of eryptosis is an increase in cytosolic Ca(2+) activity ([Ca(2+)]i). The present study explored whether zearalenone triggers eryptosis. Erythrocyte volume was estimated from forward scatter, phosphatidylserine exposure at the erythrocyte surface from annexin-V binding, hemolysis from hemoglobin release, and [Ca(2+)]i from Fluo3 fluorescence. A 48-h exposure to zearalenone (≥25 μM) was followed by a significant increase in [Ca(2+)]i and annexin-V binding, and a significant decrease in forward scatter. The effect on annexin-V binding was significantly blunted in the nominal absence of extracellular Ca(2+). Zearalenone stimulates the suicidal erythrocyte death, an effect at least partially due to stimulation of Ca(2+) entry.

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Deoxygenation-induced and Ca2+ dependent phosphatidylserine externalisation in red blood cells from normal individuals and sickle cell patients

Cited by 79 publications

References 44 publications

Oxidative stress and phosphatidylserine exposure in red cells from patients with sickle cell anaemia

Oxidative stress and phosphatidylserine exposure in red cells from patients with sickle cell anaemia

Stimulation of Suicidal Erythrocyte Death by Sulforaphane

Ca2+-dependent suicidal erythrocyte death following zearalenone exposure

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