title: Cardiac remodeling in response to chronic iron deficiency: role of the erythropoietin receptor.
abstract: OBJECTIVE
  Anemia is a common comorbidity of patients with heart failure, and iron deficiency is known as one of the causes of anemia in heart failure. Recent studies have shown that iron deficiency alone, without overt anemia, is associated with poor outcomes in patients with heart failure. Thus, to minimize the mortality in patients with heart failure, it is important to understand the link between iron deficiency and cardiac function. Chronic untreated iron deficiency results in cardiac remodeling, and we have previously reported that erythropoietin (Epo) and cardiac Epo receptor (EpoR) signaling may be associated with its remodeling. However, the link between EpoR signaling and its remodeling remains to be elucidated. Herein, we investigated the role of EpoR signaling on cardiac remodeling in response to chronic iron deficiency.
  
  
  METHODS
  Wild-type mice and transgene-rescued EpoR-null mutant mice, which express EpoR only in the hematopoietic lineage (EpoR-restricted mice), were fed with either a normal or an iron-restricted diet, and the molecular mechanisms were investigated.
  
  
  RESULTS
  Dietary iron restriction gradually induced anemia, Epo secretion, and cardiac hypertrophy in wild-type mice. In contrast, EpoR-restricted mice fed with an iron-restricted diet exhibited anemia, left ventricular dilatation, and cardiac dysfunction compared with wild-type mice. Interestingly, altered cardiac mitochondrial biogenesis was observed in EpoR-restricted mice following iron deficiency. Moreover, cardiac p53 expression was increased in EpoR-restricted mice compared with wild-type mice following iron deficiency.
  
  
  CONCLUSIONS
  These data indicate that EpoR signaling is associated with cardiac remodeling following chronic iron deficiency.
authors.affiliation: aCardiovascular Division, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya bDepartment of Pharmacy, Hyogo University of Health Sciences, Kobe, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Naito
authors.forename: Hisashi
authors.initials: H
authors.lastname: Sawada
authors.forename: Makiko
authors.initials: M
authors.lastname: Oboshi
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Iwasaku
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Okuhara
authors.forename: Daisuke
authors.initials: D
authors.lastname: Morisawa
authors.forename: Akiyo
authors.initials: A
authors.lastname: Eguchi
authors.forename: Shinichi
authors.initials: S
authors.lastname: Hirotani
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Mano
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tsujino
authors.forename: Tohru
authors.initials: T
authors.lastname: Masuyama
mesh_terms: D018798:Anemia, Iron-Deficiency / Q000150:complications*; D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000378:metabolism; D006333:Heart Failure / Q000209:etiology* / Q000473:pathology*; D000090463:Iron Deficiencies; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology*; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D017467:Receptors, Erythropoietin; D004921:Erythropoietin