First Department of Internal Medicine, Niigata University Medical and Dental Hospital, Niigata, Japan.
Cardiovasc Drugs Ther. 2013 Apr;27(2):117-24. doi: 10.1007/s10557-013-6438-0.
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).
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.
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.
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.
虽然促红细胞生成素（EPO）已知具有血管生成和心脏保护作用，但它也会引起高血压、红细胞增多症和血小板激活，这可能会在心血管疾病患者中引起严重的不良反应。我们比较了 EPO 和其非促红细胞生成素衍生物，去唾液酸 EPO（AEPO）的血管生成作用。
在 ICR 和 C57/BL 小鼠中诱导下肢缺血。小鼠肌肉内注射 2μg/kg 的 EPO 衍生物，连续 6 或 7 天。为了评估生物学差异，使用肝素亲和柱层析分析两种 EPO 衍生物的组织亲和力。还通过肌肉内药代动力学研究分析了体内的组织亲和力。
AEPO 组缺血腿的存活率优于 EPO 组（5/13=38.5%比 1/13=7.7%，p<0.05），并且在 ICR 小鼠中观察到 AEPO 组有更多的新生血管，而 EPO 组则没有。在对照组、EPO 组和 AEPO 组中，血管/肌肉比分别为 0.50±0.34、0.61±0.32 和 2.83±1.13（p<0.0001）。另一方面，在 C57/BL 小鼠中，EPO 和 AEPO 组均观察到新生血管（p<0.001）。AEPO 在体外表达肝素亲和力，而 EPO 则没有。肌肉内注射的 EPO 逐渐减少在肌肉组织中，而 AEPO 在体内快速清除阶段数小时后，在肌肉中仍维持在 2.5ng/肌肉 1 天。
AEPO 通过其组织亲和力发挥比 EPO 更强的血管生成作用。AEPO 的给药是治疗严重肢体缺血患者的一种有前途的选择。
