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Erschienen in:

01.12.2010

Erythropoietin (EPO) Affords More Potent Cardioprotection by Activation of Distinct Signaling to Mitochondrial Kinases Compared with Carbamylated EPO

verfasst von: Takahiro Sato, Masaya Tanno, Takayuki Miki, Toshiyuki Yano, Tatsuya Sato, Kazuaki Shimamoto, Tetsuji Miura

Erschienen in: Cardiovascular Drugs and Therapy | Ausgabe 5-6/2010

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Abstract

Purpose

Erythropoietin (EPO) and its non-erythrogenic derivative, carbarmylated EPO (CEPO), have been reported to activate different receptors (homomeric EPO receptor vs. heteromeric receptor consisting of EPO receptor monomer and common β-subunit). The aim of this study was to examine differences between EPO and CEPO in efficacy of cardioprotection against infarction and in activation of pro-survival kinases.

Methods

In isolated rat hearts, infarction was induced by global ischemia followed by reperfusion. Infarct size was determined 2 h after reperfusion, and ventricular tissues for immunoblotting were sampled at 5 min after reperfusion.

Results

Pretreatment with EPO (10 units/ml) before ischemia reduced infarct size (% of risk area; %IS/AR) from 47.0 ± 2.1% of the control after 20-min ischemia to 24.7 ± 4.3% and from 62.0 ± 3.0% after 25-min ischemia to 45.5 ± 4.1%. Desialylated EPO (asialoEPO, 100 ng/ml) mimicked the protection by EPO. However, CEPO (100 ng/ml) failed to reduce infarct size after 20-min ischemia (%IS/AR = 47.5 ± 5.9%) and that after 25-min ischemia (%IS/AR = 56.1 ± 4.2%). The infarct size-limiting effect of CEPO was not shown either by increasing CEPO dose to 500 ng/ml or by shortening ischemia to 15 min. Both EPO and CEPO enhanced phosphorylation of cytosolic GSK-3β upon reperfusion. In contrast, phosphorylation of GSK-3β, Akt, and PKC-ε in mitochondria upon reperfusion was significantly enhanced by EPO but not by CEPO.

Conclusion

EPO affords more potent protection against infarction than does CEPO by distinct activation of signaling leading to phosphorylation of pro-survival protein kinases in mitochondria upon reperfusion.
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Metadaten
Titel
Erythropoietin (EPO) Affords More Potent Cardioprotection by Activation of Distinct Signaling to Mitochondrial Kinases Compared with Carbamylated EPO
verfasst von
Takahiro Sato
Masaya Tanno
Takayuki Miki
Toshiyuki Yano
Tatsuya Sato
Kazuaki Shimamoto
Tetsuji Miura
Publikationsdatum
01.12.2010
Verlag
Springer US
Erschienen in
Cardiovascular Drugs and Therapy / Ausgabe 5-6/2010
Print ISSN: 0920-3206
Elektronische ISSN: 1573-7241
DOI
https://doi.org/10.1007/s10557-010-6265-5

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