Molecular mechanisms involved in murine bone marrow erythropoietic response to acute anaemia by bleeding
Todaro, Juan Santiago
Stoyanoff, Tania Romina
Aguirre, María V.
Brandan, Nora C.
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The underlying interactions among apoptosis, eiythroid proliferation and differentiation involved in bone marrow eiythropoietic response after an acute blood-loss have not yet been elucidated in detail. We hypothesized that Erythropoietin receptor, Bax, caspase-3, cytochrome c, Smac/DIABLO and Bcl-xL molecules play important roles at time of acute eiythropoietic need to ameliorate the hypoxic stress. Experiments were performed using in vivo murine model of anaemia induced by blood-loss in a time course study of 15 days. Haematological parameters and bone marrow cellularities were determined. Bone marrow apoptotic assays included: double fluorescent staining (acridine orange/ethidium bromide) and TUNEL. Bone marrow clonogenic assays were performed for evaluating eiythroid colony forming unif s expansión. The Eiythropoietin receptor, Bax, Bcl-xu Smac/DIABLO, caspase-3 and cytochrome c expressions were assessed by immunoblottings. Caspase-3 activity was determined with a colorimetric assay kit. Bleeding induces bone marrow apoptosis from 1 to 3 days, concomitant with Bax over-expression and Bcl-xL decrease. The mitochondrial dysfunction caused cytochrome c and Smac/DIABLO release to cytosol and caspase-3 activation. Eiythropoietic recoveiy was associated with Eiythropoietin receptor over expression from the third day, concomitant with the eiythroid progenitors and Bcl-xL/Bax ratio enhancements. Eiythropoiesis after bleeding depends on a delicate balance among proapoptotic (Bax, caspase-3, cytochrome c, Smac/DIABLO) and prosurvival proteins (Eiythropoietin receptor, Bcl-xL), as the crucial regulators in bone marrow eiythroid recoveiy. These findings provide new insights into the homeostatic mechanisms which promote eiythropoietic response post-bleeding.
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