title: Asialoerythropoietin, a nonerythropoietic derivative of erythropoietin, displays broad anti-heart failure activity.
abstract: BACKGROUND
  We investigated the effects of asialoerythropoietin (asialoEPO), a nonerythrogenic erythropoietin derivative, on 3 murine models of heart failure with different etiologies.
  
  
  RESULTS
  Doxorubicin (15 mg/kg) induced heart failure within 2 weeks (toxic cardiomyopathy). Treatment with asialoEPO (6.9 μg/kg) for 2 weeks thereafter attenuated the associated left ventricular dysfunction and dilatation. In addition, the asialoEPO-treated heart showed less myocardial fibrosis, inflammation, and oxidative damage, and diminished atrophic cardiomyocyte degeneration, which was accompanied by restored expression of GATA-4 and sarcomeric proteins. Mice with large 6-week-old myocardial infarctions exhibited marked left ventricular dysfunction with adverse remodeling (ischemic cardiomyopathy). AsialoEPO treatment for 4 weeks significantly mitigated progression of the dysfunction and remodeling and reduced myocardial fibrosis, inflammation, and oxidative damage. Finally, 25-week-old δ-sarcoglycan-deficient mice (genetic cardiomyopathy) were treated with asialoEPO for 5 weeks. AsialoEPO mitigated the progressive cardiac remodeling and dysfunction through cardiomyocyte hypertrophy, and upregulated expression of GATA-4 and sarcomeric proteins. AsialoEPO appears to act by altering the activity of the downstream erythropoietin receptor signals extracellular signal-regulated protein kinase, Akt, signal transducer, and activator of transcription 3 and 5 in a model-specific manner.
  
  
  CONCLUSIONS
  The findings suggest that asialoEPO exerts broad cardioprotective effects through distinct mechanisms depending on the model, which are independent of the erythrogenic action. This compound may be promising for the treatment of heart failure of various etiologies.
authors.affiliation: Department of Cardiology, Gifu University Graduate School of Medicine, 1–1 Yanagido, Gifu 501-1194, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Takeyama
authors.forename: Genzou
authors.initials: G
authors.lastname: Takemura
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kanamori
authors.forename: Tomonori
authors.initials: T
authors.lastname: Kawaguchi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ogino
authors.forename: Takatomo
authors.initials: T
authors.lastname: Watanabe
authors.forename: Kentaro
authors.initials: K
authors.lastname: Morishita
authors.forename: Akiko
authors.initials: A
authors.lastname: Tsujimoto
authors.forename: Kazuko
authors.initials: K
authors.lastname: Goto
authors.forename: Rumi
authors.initials: R
authors.lastname: Maruyama
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ushikoshi
authors.forename: Masanori
authors.initials: M
authors.lastname: Kawasaki
authors.forename: Kazunari
authors.initials: K
authors.lastname: Yamada
authors.forename: Hideki
authors.initials: H
authors.lastname: Nikami
authors.forename: Takako
authors.initials: T
authors.lastname: Fujiwara
authors.forename: Hisayoshi
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Shinya
authors.initials: S
authors.lastname: Minatoguchi
mesh_terms: D000818:Animals; D001212:Asialoglycoproteins / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005500:Follow-Up Studies; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016896:Treatment Outcome; D016277:Ventricular Function, Left / Q000187:drug effects* / Q000502:physiology; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D001212:Asialoglycoproteins; C500605:asialoerythropoietin; D004921:Erythropoietin