Oxidative Stress-Induced Membrane Shedding from RBCs is Ca Flux-Mediated and Affects Membrane Lipid Composition |
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Authors: | Inna?Freikman Israel?Ringel Email author" target="_blank">Eitan?FibachEmail author |
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Institution: | (1) Institute of Drug Research, School of Pharmacy, Hebrew University of Jerusalem, 91120 Jerusalem, Israel;(2) Department of Hematology, Hadassah–Hebrew University Medical Center, 91120 Jerusalem, Israel; |
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Abstract: | Phosphatidylserine (PS), which is normally localized in the cytoplasmic leaflet of the membrane, undergoes externalization
during aging or trauma of red blood cells (RBCs). A fraction of this PS is shed into the extracellular milieu. Both PS externalization and shedding are modulated by the
oxidative state of the cells. In the present study we investigated the effect of calcium (Ca) flux on oxidative stress-induced
membrane distribution of PS and its shedding and on the membrane composition and functions. Normal human RBCs were treated
with the oxidant t-butyl hydroperoxide, and thalassemic RBCs, which are under oxidative stress, were treated with the antioxidant vitamin C
or N-acetylcystein. The intracellular Ca content was modulated by the Ca ionophore A23187 and by varying the Ca concentration
in the medium. Ca flux was measured by Fluo-3, PS externalization and shedding were measured by quantitative flow cytometry
and membrane composition was measured by 1H-NMR analysis of the cholesterol and phospholipids. The results indicated that increasing the inward Ca flux induced PS externalization
and shedding, which in turn increased the membrane cholesterol/phospholipid ratio and thereby increased the RBC osmotic resistance.
In addition, these processes modulated the susceptibility of RBCs to undergo phagocytosis by macrophages; while PS externalization
increased phagocytosis, the shed PS prevented it. These results indicate that PS redistribution and shedding from RBCs, which
are mediated by increased calcium, have profound effects on the membrane composition and properties and, thus, may control
the fate of RBCs under physiological and pathological conditions. |
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