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This Article Full Text Full Text (PDF) All Versions of this Article: 293/3/R1127    most recent 00110.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Föller, M. Articles by Lang, F. Search for Related Content PubMed PubMed Citation Articles by Föller, M. Articles by Lang, F.

GENETICALLY MODIFIED ANIMALS AND MODEL ORGANISMS

Enhanced susceptibility to suicidal death of erythrocytes from transgenic mice overexpressing erythropoietin

¹Department of Physiology, University of Tübingen, Tübingen, Germany; and ²Institute of Veterinary Physiology, Vetsuisse Faculty and Zurich Centre for Integrative Human Physiology, University of Zurich, Switzerland

Submitted 14 February 2007 ; accepted in final form 26 May 2007

Eryptosis, a suicidal death of mature erythrocytes, is characterized by decrease of cell volume, cell membrane blebbing, and breakdown of cell membrane asymmetry with phosphatidylserine exposure at the cell surface. Triggers of eryptosis include increased cytosolic Ca²⁺ activity, which could result from activation of Ca²⁺-permeable cation channels. Ca²⁺ triggers phosphatidylserine exposure and activates Ca²⁺-sensitive K⁺ channels, leading to cellular K⁺ loss and cell shrinkage. The cation channels and thus eryptosis are stimulated by Cl^– removal and inhibited by erythropoietin. The present experiments explored eryptosis in transgenic mice overexpressing erythropoietin (tg6). Erythrocytes were drawn from tg6 mice and their wild-type littermates (WT). Phosphatidylserine exposure was estimated from annexin binding and cell volume from forward scatter in fluorescence-activated cell sorting (FACS) analysis. The percentage of annexin binding was significantly larger and forward scatter significantly smaller in tg6 than in WT erythrocytes. Transgenic erythrocytes were significantly more resistant to osmotic lysis than WT erythrocytes. Cl^– removal and exposure to the Ca²⁺ ionophore ionomycin (1 µM) increased annexin binding and decreased forward scatter, effects larger in tg6 than in WT erythrocytes. The K⁺ ionophore valinomycin (10 nM) triggered eryptosis in both tg6 and WT erythrocytes and abrogated differences between genotypes. An increase of extracellular K⁺ concentration to 125 mM blunted the difference between tg6 and WT erythrocytes. Fluo-3 fluorescence reflecting cytosolic Ca²⁺ activity was larger in tg6 than in WT erythrocytes. In conclusion, circulating erythrocytes from tg6 mice are sensitized to triggers of eryptosis but more resistant to osmotic lysis, properties at least partially due to enhanced Ca²⁺ entry and increased K⁺ channel activity.

cell volume; calcium channels; phosphatidylserine; apoptosis; excessive erythrocytosis