Reactive oxygen species and phosphatidylserine externalization in murine sickle red cells

Banerjee, Tinku; Kuypers, Frans A.

doi:10.1046/j.1365-2141.2003.04781.x

Cited by 75 publications

(68 citation statements)

References 60 publications

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“…SCA is associated with increased oxidative stress, neutrophil leucocytosis and vascular endothelial dysfunction, all of which are also associated with increased PS exposure (Jain, 1985; Hebbel, 1991; Kuypers, 1998; Mutze et al , 2003; Banerjee & Kuypers, 2004; Zhang et al , 2013). Recent reviews have reinforced the view that ROS are actively involved in lipid scrambling in SCA (Cimen, 2008; Mohanty et al , 2014; Voskou et al , 2015), with limited experimental evidence supporting this assumption.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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“…Our own studies have demonstrated that oxidant-induced damage in erythrocytes activates caspase 3, which inhibits APLT, leading to PS externalization and subsequent erythrophagocytosis (9). Increased ROS generation has also been linked to impairment of APLT activity in sickle cell disease (53). Taking these findings into consideration, we investigated whether oxidant-induced ROS generation and caspase 8 activation could be directly linked to APLT activity.…”

Section: Functional Relevance Of the Translocation Of Fas Into Rafts-mentioning

confidence: 99%

Fas-, Caspase 8-, and Caspase 3-dependent Signaling Regulates the Activity of the Aminophospholipid Translocase and Phosphatidylserine Externalization in Human Erythrocytes

Mandal

Mazumder

Das

et al. 2005

Journal of Biological Chemistry

185

127

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Apoptosis and erythrocyte senescence share the common feature of exposure of phosphatidylserine (PS) in the outer leaflet of the cells. Western analysis showed that mature red cells contain Fas, FasL, Fas-associated death domain (FADD), caspase 8, and caspase 3. Circulating, aged cells showed colocalization of Fas with the raft marker proteins G␣ s and CD59; the existence of Fas-associated FasL, FADD and caspase 8; and caspase 8 and caspase 3 activity. Aged red cells had significantly lower aminophospholipid translocase activity and higher levels of PS externalization in comparison with young cells. In support of our contention that caspases play a functional role in the mature red cell, the oxidatively stressed red cell recapitulated apoptotic events, including translocation of Fas into rafts, formation of a Fas-associated complex, and activation of caspases 8 and 3. These events were independent of calpain but dependent on reactive oxygen species (ROS) as evident from the effects of the ROS scavenger N-acetylcysteine. Caspase activation was associated with loss of aminophospholipid translocase activity and with PS externalization. ROS was not generated by treatment of cells with t-butyl hydroperoxide at 10°C, and Fas did not translocate into rafts. Concomitantly, neither formation of a Fas-associated signaling complex nor caspase activation could be observed, supporting the view that translocation of Fas into rafts was the trigger for the chain of events leading to caspase 3 activation. Our data demonstrate for the first time the novel involvement of Fas/caspase 8/caspase 3-dependent signaling in an enucleated cell leading to PS externalization, a central feature of erythrophagocytosis and erythrocyte biology.

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“…The PS exposure on erythrocytes can be induced by intracellular calcium increase and the depletion of ATP and thiol-regulated modification of phospholipid translocase activity (Banerjee and Kuypers, 2004;de Jong and Kuypers, 2006;Barber et al, 2009). PS-exposing erythrocytes frequently accompany apoptotic features such as spherocytic shape change and PS-bearing microvesicle (MV) generation.…”

mentioning

confidence: 99%

“…Depletion of cellular GSH and protein thiol makes erythrocytes more susceptible to ROS, causing various abnormal conditions, including hemolysis (Beutler, 1969), shape change (Lucantoni et al, 2006), and phosphatidylserine (PS) exposure (Banerjee and Kuypers, 2004). Damaged erythrocytes are engulfed and destroyed by tissue macrophages of spleen and liver, a process called erythrophagocytosis, inducing severe anemia as observed in sickle cell anemia or other disease states (Kuypers et al, 1998;de Jong et al, 2001;Lang et al, 2007).…”

mentioning

confidence: 99%

“…Because of the frequent exposure to oxygen-rich environment, erythrocytes often become an easy target for ROS (Banerjee and Kuypers, 2004) and ROS-generating drugs (Beutler, 1969), especially in individuals with decreased glutathione (GSH) levels resulting from the genetic glucose-6-phosphate dehydrogenase deficiency (Fanello et al, 2008), chemotherapy, or other pathophysiological conditions. Depletion of cellular GSH and protein thiol makes erythrocytes more susceptible to ROS, causing various abnormal conditions, including hemolysis (Beutler, 1969), shape change (Lucantoni et al, 2006), and phosphatidylserine (PS) exposure (Banerjee and Kuypers, 2004).…”

mentioning

confidence: 99%

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A Naphthoquinone Derivative Can Induce Anemia through Phosphatidylserine Exposure-Mediated Erythrophagocytosis

Noh¹,

Park²,

Lim³

et al. 2010

J Pharmacol Exp Ther

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A naphthoquinone derivative, ␤-lapachone (␤L; 3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione), is receiving huge attention for its potent therapeutic effects against various diseases. However, during the preclinical safety evaluation, repeated oral treatment of ␤L in rats induced anemia, i.e., a significantly decreased erythrocyte count. In this study, in an effort to elucidate the mechanism underlying the ␤L-induced anemia, we investigated the effects of ␤L on erythrocytes with freshly isolated human erythrocytes in vitro and rat in vivo. ␤L did not induce erythrocyte hemolysis, indicating that direct hemotoxicity was not involved in ␤L-associated anemia. Meanwhile, phosphatidylserine (PS) exposure along with spherocytic shape change and microvesicle generation, important factors in the facilitation of erythrophagocytosis, were increased significantly by ␤L. The PS exposure on erythrocytes was from ␤L-induced reactive oxygen species generation and subsequent depletion of reduced glutathione and protein thiol, which culminated in the modified activities of phospholipid translocases, i.e., inhibition of flippase and activation of scramblase. It is important to note that coincubation of macrophage with ␤L-treated erythrocyte in vitro showed increased erythrophagocytosis, demonstrating that the removal of erythrocyte by macrophage can be facilitated by ␤L-induced PS exposure. In good accordance with these in vitro results, after oral administration of ␤L in rats, increased PS exposure and depletion of glutathione were observed along with enhanced splenic sequestration of erythrocytes. In conclusion, these results suggest that ␤L-induced anemia might be mediated through the PS exposure and subsequent erythrophagocytosis, providing novel insight into the drug-induced anemia.

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Reactive oxygen species and phosphatidylserine externalization in murine sickle red cells

Cited by 75 publications

References 60 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

Fas-, Caspase 8-, and Caspase 3-dependent Signaling Regulates the Activity of the Aminophospholipid Translocase and Phosphatidylserine Externalization in Human Erythrocytes

A Naphthoquinone Derivative Can Induce Anemia through Phosphatidylserine Exposure-Mediated Erythrophagocytosis

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