Erythropoietin receptor signaling mitigates renal dysfunction-associated heart failure by mechanisms unrelated to relief of anemia.

Abstract

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.

• Authors: Atsushi Ogino, Genzou Takemura, Masanori Kawasaki, Akiko Tsujimoto, Hiromitsu Kanamori, Longhu Li, Kazuko Goto, Rumi Maruyama, Itta Kawamura, Toshiaki Takeyama, Tomonori Kawaguchi, Takatomo Watanabe, Yoshiyuki Moriguchi, Hideki Saito, Takako Fujiwara, Hisayoshi Fujiwara, Shinya Minatoguchi
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 56 Issue 23 Pg. 1949-58 (Nov 30 2010) ISSN: 1558-3597 [Electronic] United States
• PMID: 21109120 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Chemical References

• Asialoglycoproteins
• Receptors, Erythropoietin
• Recombinant Proteins
• asialoerythropoietin
• Erythropoietin

Topics

• Anemia (complications, drug therapy, metabolism)
• Animals
• Asialoglycoproteins (therapeutic use)
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Erythropoietin (analogs & derivatives, therapeutic use)
• Heart Failure (etiology, metabolism, prevention & control)
• Male
• Mice
• Mice, Inbred C57BL
• Oxidative Stress
• Receptors, Erythropoietin (metabolism)
• Recombinant Proteins
• Renal Insufficiency (complications, drug therapy, metabolism)
• Signal Transduction