Reduction of inflammatory cytokine expression and oxidative damage by erythropoietin in chronic heart failure.
OBJECTIVE
Late treatment with erythropoietin (EPO), as well as the administration before the onset of or during the acute stage of myocardial infarction (MI), has recently been shown to mitigate post-MI heart failure. We investigated the mechanisms, including the downstream signaling pathways, for the beneficial effect of late treatment with EPO on chronic post-MI heart failure.


RESULTS
EPO (1500 U/kg, twice a week) was administered to mice beginning 6 weeks after induction of large MI. The EPO treatment for 4 weeks diminished left ventricular dilatation and improved function. It significantly reduced inflammatory cell infiltration and fibrosis, and increased vascular density in noninfarcted areas. The elevated levels of the inflammatory cytokines interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha and transforming growth factor-beta1 seen in the failing hearts were returned nearly to control levels by EPO treatment. Oxidative damage in surviving cardiomyocytes was also significantly attenuated by EPO. Expression of EPO receptor was upregulated in failing hearts, and EPO treatment led to myocardial activation of signal transducer and activator of transcription-3 (Stat3), Stat5, and Akt. These in vivo effects of EPO were confirmed in vitro in experiments that showed the anti-inflammatory and anti-oxidant effects of EPO to be mediated via Stat and Akt activation. Finally, the beneficial effects of EPO were found to persist for 4 weeks after discontinuing treatment.


CONCLUSIONS
It thus appears that Stat-mediated reduction of inflammation and cytokine production and Akt-mediated attenuation of oxidative stress accompany the beneficial effects of late treatment with EPO on chronic post-MI heart failure.
Li
Yiwen
Y
Second Department of Internal Medicine, Gifu University School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
Takemura
Genzou
G
Okada
Hideshi
H
Miyata
Shusaku
S
Maruyama
Rumi
R
Li
Longhu
L
Higuchi
Masato
M
Minatoguchi
Shinya
S
Fujiwara
Takako
T
Fujiwara
Hisayoshi
H
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004452:Echocardiography; D004921:Erythropoietin / Q000627:therapeutic use*; D005347:Fibroblasts / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D006400:Hematocrit; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D023421:Models, Animal; D009206:Myocardium / Q000276:immunology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects; D010084:Oxidation-Reduction; D011897:Random Allocation; D017467:Receptors, Erythropoietin / Q000032:analysis / Q000378:metabolism; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects; D013995:Time; D020257:Ventricular Remodeling / Q000187:drug effects
D016207:Cytokines; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D004921:Erythropoietin; D006861:Hydrogen Peroxide