Erythropoietin receptor signaling mitigates renal dysfunction-associated heart failure by mechanisms unrelated to relief of anemia.
OBJECTIVE
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.
Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan.
Atsushi
A
Ogino
Genzou
G
Takemura
Masanori
M
Kawasaki
Akiko
A
Tsujimoto
Hiromitsu
H
Kanamori
Longhu
L
Li
Kazuko
K
Goto
Rumi
R
Maruyama
Itta
I
Kawamura
Toshiaki
T
Takeyama
Tomonori
T
Kawaguchi
Takatomo
T
Watanabe
Yoshiyuki
Y
Moriguchi
Hideki
H
Saito
Takako
T
Fujiwara
Hisayoshi
H
Fujiwara
Shinya
S
Minatoguchi
D000740:Anemia / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D001212:Asialoglycoproteins / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D006333:Heart Failure / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D017467:Receptors, Erythropoietin / Q000378:metabolism*; D011994:Recombinant Proteins; D051437:Renal Insufficiency / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D015398:Signal Transduction
D001212:Asialoglycoproteins; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; C500605:asialoerythropoietin; D004921:Erythropoietin