title: Protective effects of recombinant human erythropoietin against pressure overload-induced left ventricular remodeling and premature death in mice.
abstract: Chronic left ventricular (LV) pressure overload induced by hypertension is one of the most common causes of heart failure. Earlier reports have shown the cardioprotective effects of erythropoietin (EPO). In the present study, we tested the hypothesis that recombinant human EPO exerts a protective effect against pressure-overload induced LV remodeling. Mice subjected to transverse aortic constriction (TAC) (n = 70) were randomly assigned to the treatment with phosphate buffer solution (PBS) (TAC-PBS) or EPO (2,000 U/kg twice a week) (TAC-EPO). At 8 weeks after TAC, LV weight was comparably increased in both TAC groups compared with sham-operated mice (Sham) (both P < 0.001). The treatment with EPO improved the survival of TAC mice as compared with treatment with PBS (80 vs. 47%, P < 0.01), which was associated with reductions in the extent of myocardial fibrosis and the number of TUNEL positive cardiomyocytes (both P < 0.05). Echocardiography revealed that TAC increased LV chamber diameter and decreased LV fractional shortening compared with Sham (P < 0.05), which was ameliorated by the treatment with EPO (P < 0.05). In TAC-EPO as compared to TAC-PBS, phosphorylation of STAT3, Akt and eNOS was all increased, while phosphorylation of p38 was decreased (all P < 0.05). Importantly, the expression level of VEGF and the capillary density in LV myocardium were similar among the 3 groups. These results suggest that recombinant human EPO ameliorates the cardiac remodeling and the premature death associated with chronic LV pressure overload through the mechanisms independent of angiogenesis.
authors.affiliation: Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Wanting
authors.initials: W
authors.lastname: Wang
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kagaya
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Asaumi
authors.forename: Shigefumi
authors.initials: S
authors.lastname: Fukui
authors.forename: Morihiko
authors.initials: M
authors.lastname: Takeda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology; D004195:Disease Models, Animal; D004452:Echocardiography; D004921:Erythropoietin / Q000494:pharmacology*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006439:Hemodynamics / Q000187:drug effects; D008136:Longevity / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D061213:Mortality, Premature; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D011994:Recombinant Proteins / Q000008:administration & dosage; D015996:Survival Rate; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
chemical_list: D015415:Biomarkers; C554270:EPO protein, human; D011994:Recombinant Proteins; D004921:Erythropoietin