Side effects of peroxisome proliferator activated receptor gamma (PPARγ) agonists such as ciglitazone include anemia, which in theory could be due to decreased formation or premature death of erythrocytes. A form of suicidal erythrocyte death is eryptosis, which is characterized by cell shrinkage and by breakdown of phosphatidylserine asymmetry leading to phosphatidylserine exposure at the cell surface. Phosphatidylserine-exposing erythrocytes are recognized by macrophages, engulfed, degraded and thus cleared from circulating blood. Triggers of eryptosis include increase in intracellular Ca2+ concentration. The present study thus explored, whether the PPARγ agonist ciglitazone or the natural PPARγ ligand 15deoxy-delta12,14-prostaglandin J2 (15d-PGJ2) are capable to trigger eryptosis. Phosphatidylserine exposure was determined from annexin V binding and cell shrinkage from decrease of forward scatter of human erythrocytes in FACS analysis. Both, ciglitazone (≧ 5 µM) and 15d-PGJ2 (≧ 3 µM), within 24 hours increased phosphatidylserine exposure and at concentrations of 10 µM led to a significant loss of the cell volume. Ciglitazone further stimulated hemolysis, which, however, affected only a fraction of erythrocytes undergoing eryptosis. According to Fluo3 fluorescence of human erythrocytes, 10 µM ciglitazone or 15d-PGJ2 increased intracellular Ca2+ activity. In conclusion, ciglitazone and 15d-PGJ2 trigger eryptosis at least in part by an increase in the cytosolic Ca2+ concentration. The effect most likely contributes to the anemia observed following treatment with PPARγ agonists.

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