Erythropoietin Receptor Signaling Mitigates Renal Dysfunction-Associated Heart Failure by Mechanisms Unrelated to Relief of Anemia

Abstract

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.

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

“…We previously reported that asialoEPO restored GATA-4 expression in CKD-associated heart failure. 14 We suggest that the beneficial effects of asialoEPO on GATA-4 expression, myofibrillar content, and sarcomeric integrity are key elements underlying the observed improvement in cardiac function in the failing hearts, as these changes would directly influence the contractile power of individual cardiomyocytes. AsialoEPO indicates asialoerythropoietin; 2, the strength of the phenotype is less than in the sham or wild type; 1, the strength of the phenotype is greater than in the sham or wild type; 3, the strength of the phenotype is similar to the sham or wild type.…”

“…*Data on nephrectomy-induced heart failure from Ogino et al 14 Induction of powerful inflammatory mediators is reportedly associated with heart failure. 19,20 Inflammatory reactions often are associated with oxidative stress in a vicious cycle in which inflammatory mediators and various oxidants induce and exacerbate one another.…”

“…13 In addition, we recently demonstrated that asialoEPO attenuates nephrectomy induced left ventricular remodeling and dysfunction without increasing hemoglobin levels. 14 These findings underscore the fact that the EPO-mediated improvement of cardiac function is not mediated through increased hemoglobin levels, but through pleiotropic effects. 14,15 We therefore hypothesized that systemically administered asialoEPO would exert therapeutic effects on models of established heart failure having different etiologies by acting through cardioprotective mechanisms that do not involve increasing hemoglobin levels.…”

“…14 These findings underscore the fact that the EPO-mediated improvement of cardiac function is not mediated through increased hemoglobin levels, but through pleiotropic effects. 14,15 We therefore hypothesized that systemically administered asialoEPO would exert therapeutic effects on models of established heart failure having different etiologies by acting through cardioprotective mechanisms that do not involve increasing hemoglobin levels. To test that idea, we examined the effect of asialoEPO on doxorubicin induced toxic cardiomyopathy, postlarge myocardial infarction ischemic cardiomyopathy, and ␦-sarcoglycan-deficient genetic cardiomyopathy.…”

A novel synthetic derivative of human erythropoietin designed to bind to glycosaminoglycans

“…37 AEPO is one of the candidates to avoid platelet activation because the serum level of AEPO does not elevate while preserving their angiogenic (PCT Patent 2006/129755) and cardioprotective effects but not erythropoietic effects. 38 HEPO is another candidate. HEPO reveals tissue affinity, and thus probably does not to show a rapid rise in blood.…”