Enhanced Erythrocyte Apoptosis in Sickle Cell Anemia, Thalassemia and Glucose-6-Phosphate Dehydrogenase Deficiency

Abstract

Erythrocyte diseases such as sickle cell anemia, thalassemia and glucose-6-phosphate dehydrogenase deficiency decrease the erythrocyte life span, an effect contributing to anemia. Most recently, erythro-cytes have been shown to undergo apoptosis upon increase of cytosolic Ca²⁺ activity. The present study has been performed to explore whether sickle cell anemia, thalassemia and glucose-6-phosphate dehydrogenase deficiency enhance the sensitivity of erythrocytes to osmotic shock, oxidative stress or energy depletion, all maneuvers known to increase cytosolic Ca²⁺ activity. To this end, annexin binding as an indicator of apoptosis has been determined by FACS analysis. Erythrocytes from healthy individuals, from patients with sickle cell anemia, thalassemia or glucose-6-phosphate dehydrogenase deficiency all responded to osmotic shock (up to 950 mOsm by addition of sucrose for 24 hours), to oxidative stress (up to 1.0 mM tetra-butyl-hydroxyperoxide tBOOH) and to energy depletion (up to 48 hours glucose deprivation) with enhanced annexin binding. However, the sensitivity of sickle cells and of glucose-6-phosphate dehydrogenase deficient cells to osmotic shock and of sickle cells, thalassemic cells and glucose-6-phosphate dehydrogenase deficient cells to oxidative stress and to glucose depletion was significantly higher than that of control cells. Annexin binding was further stimulated by Ca²⁺ ionophore ionomycin with significantly higher sensitivity of sickle cells and glucose-6-phosphate dehydrogenase deficient cells as compared to intact cells. In conclusion, sickle cells, thalassemic cells and glucose-6-phosphate dehydrogenase deficient erythrocytes are more sensitive to osmotic shock, oxidative stress and/or energy depletion, thus leading to enhanced apoptosis of those cells. The accelerated apoptosis then contributes to the shortened life span of the defective erythrocytes.

Escherichia coli α-Hemolysin Triggers Shrinkage of Erythrocytes via KCa3.1 and TMEM16A Channels with Subsequent Phosphatidylserine Exposure

“…Through the clear correlation between PS exposure, cell size, and cell age, it has been shown that macrophages use specific detection of PS exposure to eliminate senescent erythrocytes from the circulation (35,36). Acute damage to the erythrocytes by Ca 2ϩ ionophores, energy depletion, oxidative stress, osmotic shock, and malaria infections provoke shrinkage of erythrocytes and/or PS exposure (16,32,33,(37)(38)(39). Thus, it seems that both senescent and acutely damaged red blood cells are eliminated through the same pathway, and we speculate that K Ca 3.1 and TMEM16A activation allow early recognition and removal of erythrocytes attacked by HlyA.…”

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

“…A fourth oxidant, t BHP, generates peroxyl and alkoxyl derivatives (Davies, 1989) and has previously been reported to increase PS exposure in red cells from SCA patients – using a concentration of up to 1 mmol/l in a 2‐h incubation (Lang et al , 2002). This oxidant behaved differently to the previous three.…”

“…Finally, red cells from SCA patients have been previously described to show increased PS exposure on incubation with t BHP (Lang et al , 2002). The concentrations used in this previous report were up to 1 mmol/l, however, with an incubation time of 2 h, after which all red cells were positive for PS (labelled using FITC‐ annexin V).…”

“…Oxidative damage has long been associated with PS exposure in red cells (Jain & Shohet, 1984; Jain & Williams, 1985; Kuypers, 1998; Lang et al , 2002, 2012). This is particularly significant in diseases such as SCA in which vascular oxidative stress is increased (Rice‐Evans et al , 1986) with accumulations of highly reactive oxygen species (ROS) including the superoxide anion, hydrogen peroxide and the hydroxyl radical (Sies, 1997; Chirico & Pialoux, 2012; Voskou et al , 2015).…”

Anemia and splenomegaly in cGKI-deficient mice

“…A decrease of NO-dependent activation of cGKI could participate in the pathophysiology of those conditions. Moreover, accelerated eryptosis participates in the pathophysiology of iron deficiency (32), hemolytic uremic syndrome (49), sepsis (50), malaria (51), Wilson's disease (52), thalassemia (53), glucose-phosphate dehydrogenase deficiency (53), and diabetes (54). At least in theory, stimulation of cGKI could reverse accelerated eryptosis in those diseases.…”