Abstract 8771: Asialoerythropoietin, a Nonerythropoietic Derivative of Erythropoietin, Displays Broad Anti-Heart Failure Activity

Abstract

Accumulating evidence suggests cardioprotective effect of erythropoietion (EPO) in experiments, but EPO has some unwanted effects. We investigated effect of asialoerythropoietin (AEPO), a nonerythrogenic derivative of EPO, on 3 different models of heart failure: doxorubicin (DOX)-induced cardiomyopathy, post-large myocardial infarction (MI), and dilated cardiomyopathy in δ-sarcoglycan deficient mouse (Sgcd-null). Accoding to echocardiography and cardiac catheterization, a single intraperitoneal injection of DOX (15 mg/kg) induced an established heart failure in mice 2 weeks later, to which AEPO (1500 U/kg, twice a week, for 2 weeks) was administered. Left ventricular dysfunction was attenuated in the AEPO-treated group (ejection fraction: 71±3% vs. 50±1% in controls). The AEPO-treated heart showed less myocardial fibrosis, inflammatory cell infiltration, and atrophic degeneration of cardiomyocytes accompanying restored expression of GATA-4 and sarcomeric proteins. Among downstream signals of EPO receptor, DOX inactivated ERK in the heart, of which activity AEPO restored. Next, in the mice with large sized, 6-week-old MI, a marked left ventricular dysfunction with adverse remodeling was apparent. AEPO treatment for the subsequent 4 weeks mitigated the further progression of dysfunction and remodeling (ejection fraction: 37±2% vs. 26±3% in controls), accompanying reduced myocardial fibrosis. ERK and Akt were activated in the MI bearing hearts, which were furthermore augmented by AEPO. AEPO activated STAT3, too. Finally, AEPO was administered to 25 weeks old Sgcd-null mice with decreased left ventricular contractility, for the subsequent 5 weeks. Left ventricular dysfunction and dilatation were mitigated (ejection fraction: 71±1% vs. 52±0.4% in controls), accompanying reduced myocardial fibrosis and furthermore compensative hypertrophy. ERK was inactivated, and Akt was activated in the heart of Sgcd null mice. AEPO restored the ERK activity, and furthermore activated Akt. Neither polycythemia nor splenomegaly was noted in any groups. In conclusion, AEPO displays broad anti-heart failure activity regardless of the etiology of heart failure through distinct molecular signals.