Key result
rhEPO and asialoEPO mitigate LV dilation and dysfunction in mice independent of anemia relief.
Why the study?
Clinical benefits of erythropoietin in chronic kidney disease are controversial, leaving it unclear whether outcomes stem from relief of anemia, adverse effects, or direct cardiovascular actions.
Does erythropoietin receptor signaling mitigate renal dysfunction-associated heart failure in mice?
Does erythropoietin receptor signaling mitigate renal dysfunction-associated heart failure in mice?
Erythropoietin receptor signaling exerts direct cardioprotective effects in renal dysfunction-associated heart failure independent of its effects on anemia.
Supports EPO receptor agonism for direct cardioprotection in murine cardiorenal HF; hypothesis-generating and leaves open human translation.
OBJECTIVES: We examined the effect of asialoerythropoietin (asialoEPO), a nonerythrogenic derivative of erythropoietin (EPO), on renal dysfunction-associated heart failure. BACKGROUND: Although EPO is known to exert beneficial effects on cardiac function, the clinical benefits in patients with chronic kidney disease are controversial. It remains to be addressed whether previously reported outcomes were the result of relief of the anemia, adverse effects of EPO, or direct cardiovascular effects. METHODS: Mice underwent 5/6 nephrectomy to cause renal dysfunction. Eight weeks later, when renal dysfunction was established, anemia and cardiac dysfunction and remodeling were apparent. Mice were then assigned to receive saline (control), recombinant human erythropoietin (rhEPO) at 5,000 IU (714 pmol)/kg, or asialoEPO at 714 pmol/kg, twice/week for 4 weeks. RESULTS: Although only rhEPO relieved the nephrectomy-induced anemia, both rhEPO and asialoEPO significantly and similarly mitigated left ventricular dilation and dysfunction. The hearts of rhEPO- or asialoEPO-treated mice showed less hypertrophy, reflecting decreases in cardiomyocyte hypertrophy and degenerative subcellular changes, as well as significant attenuation of fibrosis, leukocyte infiltration, and oxidative deoxyribonucleic acid damage. These phenotypes were accompanied by restored expression of GATA-4, sarcomeric proteins, and vascular endothelial growth factor and decreased inflammatory cytokines and lipid peroxidation. Finally, myocardial activation was observed of extracellular signal-regulated protein kinase and signal transducer and activator of transcription pathways in the treated mice. CONCLUSIONS: EPO receptor signaling exerts direct cardioprotection in an animal model of renal dysfunction-associated heart failure, probably by mitigating degenerative, pro-fibrosis, inflammatory, and oxidative processes but not through relief of anemia.
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Ogino et al. (2010) studied Renal dysfunction-associated heart failure. asialoerythropoietin (asialoEPO) and recombinant human erythropoietin (rhEPO) vs. saline (control) was evaluated on left ventricular dilation and dysfunction. In a mouse model of renal dysfunction-associated heart failure, both rhEPO and asialoEPO significantly mitigated left ventricular dilation and dysfunction, independent of anemia relief.