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Asialoerythropoietin Exerts Stronger Angiogenic Activity than Erythropoietin Via its Binding Affinity to Tissue

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Abstract

Purpose

Although erythropoietin (EPO) is known to express angiogenic and cardioprotective effects, it also induces hypertension, polycythemia, and platelet activation, which may cause serious adverse effects in patients with cardiovascular diseases. We compared the angiogenic effects of EPO and its nonerythropoietic derivative, asialo-EPO (AEPO).

Methods

Lower limb ischemia was induced in ICR and C57/BL mice. Mice were injected intramuscularly with 2 μg/kg of EPO derivatives for 6 or 7 days. To assess biological differences, the tissue affinity of both EPO derivatives was analyzed in vitro using heparin affinity column chromatography. Tissue affinity was also analyzed in vivo using an intramuscular pharmacokinetic study.

Results

The survival of ischemic legs was better in the AEPO group than that in the EPO group (5/13 = 38.5 % vs 1/13 = 7.7 %, p < 0.05), and an increase in regenerated vessels was observed in the AEPO group, but not in the EPO group in ICR mice. Vessel/muscle ratios in control, EPO, and AEPO groups were 0.50 ± 0.34, 0.61 ± 0.32, and 2.83 ± 1.13, respectively (p < 0.0001). On the other hand, regenerated vessels were observed in both EPO and AEPO groups (p < 0.001) in C57/BL mice. AEPO, but not EPO, expressed heparin affinity in vitro. Intramuscularly injected EPO gradually decreased in muscle tissue, while AEPO was maintained at 2.5 ng/muscle for 1 day after several hours of a rapid clearance phase in vivo.

Conclusions

AEPO exerts stronger angiogenic effects than those of EPO presumably via its tissue affinity. Administration of AEPO is a promising option for the treatment of patients with critical limb ischemia.

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Acknowledgements

This work was supported in part by Grants-in-Aid for scientific research from The Ministry of Education in Japan (grant nos. 21590887 and 19590856 to K.T., 21590888 to T.O., 18590806 to K.K.).

Conflict of interest

All authors have no conflict of interest.

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Authors and Affiliations

  1. First Department of Internal Medicine, Niigata University Medical and Dental Hospital, Niigata, Japan

    Takao Yanagawa, Ken Toba, Kiminori Kato, Tomoyasu Suzuki, Shiro Minagawa, Takashi Saigawa, Takuya Ozawa, Masato Oda, Tsugumi Takayama, Haruo Hanawa & Yoshifusa Aizawa

  2. Product Research Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan

    Masato Higuchi & Hideki Saito

  3. Division of Hematology, Niigata University Graduate School of Medical and Dental Sciences, 1-754 Asahimachi, Niigata, 951-8510, Japan

    Ken Toba

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  1. Takao Yanagawa
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Correspondence to Ken Toba.

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Yanagawa, T., Toba, K., Kato, K. et al. Asialoerythropoietin Exerts Stronger Angiogenic Activity than Erythropoietin Via its Binding Affinity to Tissue. Cardiovasc Drugs Ther 27, 117–124 (2013). https://doi.org/10.1007/s10557-013-6438-0

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  • DOI: https://doi.org/10.1007/s10557-013-6438-0

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