title: Females Are Protected From Iron-Overload Cardiomyopathy Independent of Iron Metabolism: Key Role of Oxidative Stress.
abstract: Sex-related differences in cardiac function and iron metabolism exist in humans and experimental animals. Male patients and preclinical animal models are more susceptible to cardiomyopathies and heart failure. However, whether similar differences are seen in iron-overload cardiomyopathy is poorly understood.
  
  
  
  Male and female wild-type and hemojuvelin-null mice were injected and fed with a high-iron diet, respectively, to develop secondary iron overload and genetic hemochromatosis. Female mice were completely protected from iron-overload cardiomyopathy, whereas iron overload resulted in marked diastolic dysfunction in male iron-overloaded mice based on echocardiographic and invasive pressure-volume analyses. Female mice demonstrated a marked suppression of iron-mediated oxidative stress and a lack of myocardial fibrosis despite an equivalent degree of myocardial iron deposition. Ovariectomized female mice with iron overload exhibited essential pathophysiological features of iron-overload cardiomyopathy showing distinct diastolic and systolic dysfunction, severe myocardial fibrosis, increased myocardial oxidative stress, and increased expression of cardiac disease markers. Ovariectomy prevented iron-induced upregulation of ferritin, decreased myocardial SERCA2a levels, and increased NCX1 levels. 17β-Estradiol therapy rescued the iron-overload cardiomyopathy in male wild-type mice. The responses in wild-type and hemojuvelin-null female mice were remarkably similar, highlighting a conserved mechanism of sex-dependent protection from iron-overload-mediated cardiac injury.
  
  
  
  Male and female mice respond differently to iron-overload-mediated effects on heart structure and function, and females are markedly protected from iron-overload cardiomyopathy. Ovariectomy in female mice exacerbated iron-induced myocardial injury and precipitated severe cardiac dysfunction during iron-overload conditions, whereas 17β-estradiol therapy was protective in male iron-overloaded mice.
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.|Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Subhash K
authors.initials: SK
authors.lastname: Das
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.|Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Vaibhav B
authors.initials: VB
authors.lastname: Patel
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.|Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Ratnadeep
authors.initials: R
authors.lastname: Basu
authors.affiliation: Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.|Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Wang
authors.initials: W
authors.lastname: Wang
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.|Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jessica
authors.initials: J
authors.lastname: DesAulniers
authors.affiliation: Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.|Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada gavin.oudit@ualberta.ca.|Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.|Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000000981:diagnostic imaging / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D004032:Diet; D004452:Echocardiography; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005293:Ferritins / Q000378:metabolism; D005355:Fibrosis; D058851:GPI-Linked Proteins; D006321:Heart / Q000187:drug effects; D054144:Heart Failure, Diastolic / Q000000981:diagnostic imaging / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D006432:Hemochromatosis / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D000071020:Hemochromatosis Protein; D019190:Iron Overload / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology; D010052:Ovariectomy; D018384:Oxidative Stress / Q000187:drug effects; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D012737:Sex Factors; D019831:Sodium-Calcium Exchanger / Q000378:metabolism
chemical_list: D058851:GPI-Linked Proteins; C504414:HJV protein, mouse; D000071020:Hemochromatosis Protein; D008565:Membrane Proteins; C499849:NCX1 protein, mouse; D019831:Sodium-Calcium Exchanger; D004958:Estradiol; D005293:Ferritins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
keywords: 17‐β‐estradiol; heart failure; hemojuvelin; iron overload; myocardial fibrosis; ovariectomy; oxidative stress; sex