Targeting erythroblast-specific apoptosis in experimental anemia.
Erythrocyte production is regulated by balancing precursor cell apoptosis and survival signaling. Previously, we found that BH3-only proapoptotic factor, Nix, opposed erythroblast-survival signaling by erythropoietin-induced Bcl-xl during normal erythrocyte formation. Since erythropoietin treatment of human anemia has limitations, we explored the therapeutic potential of abrogating Nix-mediated erythroblast apoptosis to enhance erythrocyte production. Nix gene ablation blunted the phenylhydrazine-induced fall in blood count, enhanced hematocrit recovery, and reduced erythroblast apoptosis, despite lower endogenous erythropoietin levels. Similar to erythropoietin, Nix ablation increased early splenic erythroblasts and circulating reticulocytes, while maintaining a pool of mature erythroblasts as erythropoietic reserve. Erythrocytes in Nix-deficient mice showed morphological abnormalities, suggesting that apoptosis during erythropoiesis not only controls red blood cell number, but also serves a "triage" function, preferentially eliminating abnormal erythrocytes. These results support the concept of targeting erythroblast apoptosis to maximize erythrocyte production in acute anemia, which may be of value in erythropoietin resistance.
Diwan
Abhinav
A
Center for Molecular Cardiovascular Research, University of Cincinnati, Cincinnati, OH, USA.
Koesters
Andrew G
AG
Capella
Devan
D
Geiger
Hartmut
H
Kalfa
Theodosia A
TA
Dorn
Gerald W
GW
D000740:Anemia / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001853:Bone Marrow / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D004900:Erythroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004906:Erythrocyte Count; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004921:Erythropoietin / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D018390:Gene Targeting; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics*; D016877:Oxidants / Q000494:pharmacology; D010659:Phenylhydrazines / Q000494:pharmacology; D020127:Recovery of Function / Q000187:drug effects / Q000235:genetics
D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C501741:Nix protein, mouse; D016877:Oxidants; D010659:Phenylhydrazines; C030299:phenylhydrazine; D004921:Erythropoietin