Copyright © 2006, European Society of Cardiology
Reduction of inflammatory cytokine expression and oxidative damage by erythropoietin in chronic heart failure
aSecond Department of Internal Medicine, Gifu University School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan
bProduct Research Department, Chugai Pharmaceutical Co. Ltd., Shizuoka, Japan
cDepartment of Food Science, Kyoto Women's University, Kyoto, Japan
dKidney Disease Center, The 1st Affiliated Hospital of Medical College Zhejiang University, Hangzhou, Zhejiang, P. R. China
* Corresponding author. Tel.: +81 58 230 6520; fax: +81 58 230 6521. Email address: gifuim-gif{at}umin.ac.jp
Objectives 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.
Methods and 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)-1β, IL-6, tumor necrosis factor-
and transforming growth factor-β1 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.
KEYWORDS Cytokines; Heart failure; Myocardial infarction; Myocardial inflammation
Time for primary review 19 days
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