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Killing me softly - suicidal erythrocyte death.


Similar to nucleated cells, erythrocytes may undergo suicidal death or eryptosis, which is characterized by cell shrinkage, cell membrane blebbing and cell membrane phospholipid scrambling. Eryptotic cells are removed and thus prevented from undergoing hemolysis. Eryptosis is stimulated by Ca(2+) following Ca(2+) entry through unspecific cation channels. Ca(2+) sensitivity is enhanced by ceramide, a product of acid sphingomyelinase. Eryptosis is triggered by hyperosmolarity, oxidative stress, energy depletion, hyperthermia and a wide variety of xenobiotics and endogenous substances. Eryptosis is inhibited by nitric oxide, catecholamines and a variety of further small molecules. Erythropoietin counteracts eryptosis in part by inhibiting the Ca(2+)-permeable cation channels but by the same token may foster formation of erythrocytes, which are particularly sensitive to eryptotic stimuli. Eryptosis is triggered in several clinical conditions such as iron deficiency, diabetes, renal insufficiency, myelodysplastic syndrome, phosphate depletion, sepsis, haemolytic uremic syndrome, mycoplasma infection, malaria, sickle-cell anemia, beta-thalassemia, glucose-6-phosphate dehydrogenase-(G6PD)-deficiency, hereditary spherocytosis, paroxysmal nocturnal hemoglobinuria, and Wilson's disease. Enhanced eryptosis is observed in mice with deficient annexin 7, cGMP-dependent protein kinase type I (cGKI), AMP-activated protein kinase AMPK, anion exchanger AE1, adenomatous polyposis coli APC and Klotho as well as in mouse models of sickle cell anemia and thalassemia. Eryptosis is decreased in mice with deficient phosphoinositide dependent kinase PDK1, platelet activating factor receptor, transient receptor potential channel TRPC6, janus kinase JAK3 or taurine transporter TAUT. If accelerated eryptosis is not compensated by enhanced erythropoiesis, clinically relevant anemia develops. Eryptotic erythrocytes may further bind to endothelial cells and thus impede microcirculation.