title: Asialoerythropoietin exerts stronger angiogenic activity than erythropoietin via its binding affinity to tissue.
abstract: OBJECTIVE
  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.
authors: First Department of Internal Medicine, Niigata University Medical and Dental Hospital, Niigata, Japan.
authors: Takao
authors: T
authors: Yanagawa
authors: Ken
authors: K
authors: Toba
authors: Kiminori
authors: K
authors: Kato
authors: Tomoyasu
authors: T
authors: Suzuki
authors: Shiro
authors: S
authors: Minagawa
authors: Takashi
authors: T
authors: Saigawa
authors: Takuya
authors: T
authors: Ozawa
authors: Masato
authors: M
authors: Oda
authors: Tsugumi
authors: T
authors: Takayama
authors: Haruo
authors: H
authors: Hanawa
authors: Masato
authors: M
authors: Higuchi
authors: Hideki
authors: H
authors: Saito
authors: Yoshifusa
authors: Y
authors: Aizawa
mesh_terms: D000818:Animals; D001212:Asialoglycoproteins / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004921:Erythropoietin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006493:Heparin / Q000378:metabolism; D007273:Injections, Intramuscular; D007511:Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011485:Protein Binding
chemical_list: D001212:Asialoglycoproteins; C500605:asialoerythropoietin; D004921:Erythropoietin; D006493:Heparin