title: Ciglitazone and 15d-PGJ2 induced suicidal erythrocyte death.
abstract: Side effects of peroxisome proliferator activated receptor gamma (PPARgamma) 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 Ca(2+) concentration. The present study thus explored, whether the PPARgamma agonist ciglitazone or the natural PPARgamma 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 (>or= 5 microM) and 15d-PGJ2 (>or= 3 microM), within 24 hours increased phosphatidylserine exposure and at concentrations of 10 microM 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 microM ciglitazone or 15d-PGJ2 increased intracellular Ca(2+) activity. In conclusion, ciglitazone and 15d-PGJ2 trigger eryptosis at least in part by an increase in the cytosolic Ca(2+) concentration. The effect most likely contributes to the anemia observed following treatment with PPARgamma agonists.
authors.affiliation: Department of Physiology, University of Tübingen, Germany.
authors.forename: Olivier M
authors.initials: OM
authors.lastname: Niemoeller
authors.forename: Hasan
authors.initials: H
authors.lastname: Mahmud
authors.forename: Michael
authors.initials: M
authors.lastname: Föller
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieder
authors.forename: Florian
authors.initials: F
authors.lastname: Lang