title: mRNA regulation of cardiac iron transporters and ferritin subunits in a mouse model of iron overload.
abstract: Iron cardiomyopathy is the leading cause of death in iron overload. Men have twice the mortality rate of women, though the cause is unknown. In hemojuvelin-knockout mice, a model of the disease, males load more cardiac iron than females. We postulated that sex differences in cardiac iron import cause differences in cardiac iron concentration. Reverse transcription polymerase chain reaction was used to measure mRNA of cardiac iron transporters in hemojuvelin-knockout mice. No sex differences were discovered among putative importers of nontransferrin-bound iron (L-type and T-type calcium channels, ZRT/IRT-like protein 14 zinc channels). Transferrin-bound iron transporters were also analyzed; these are controlled by the iron regulatory element/iron regulatory protein (IRE/IRP) system. There was a positive relationship between cardiac iron and ferroportin mRNA in both sexes, but it was significantly steeper in females (p < 0.05). Transferrin receptor 1 and divalent metal transporter 1 were more highly expressed in females than males (p < 0.01 and p < 0.0001, respectively), consistent with their lower cardiac iron levels, as predicted by IRE/IRP regulatory pathways. Light-chain ferritin showed a positive correlation with cardiac iron that was nearly identical in males and females (R(2) = 0.41, p < 0.01; R(2) = 0.56, p < 0.05, respectively), whereas heavy-chain ferritin was constitutively expressed in both sexes. This represents the first report of IRE/IRP regulatory pathways in the heart. Transcriptional regulation of ferroportin was suggested in both sexes, creating a potential mechanism for differential set points for iron export. Constitutive heavy-chain-ferritin expression suggests a logical limit to cardiac iron buffering capacity at levels known to produce heart failure in humans.
authors.affiliation: Division of Pediatric Cardiology, Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors.forename: Casey J
authors.initials: CJ
authors.lastname: Brewer
authors.affiliation: Department of Cell and Neurobiology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
authors.forename: Ruth I
authors.initials: RI
authors.lastname: Wood
authors.affiliation: Division of Pediatric Cardiology, Children's Hospital Los Angeles, Los Angeles, CA, USA. Electronic address: jwood@chla.usc.edu.
authors.forename: John C
authors.initials: JC
authors.lastname: Wood
mesh_terms: D000818:Animals; D001052:Apoferritins / Q000096:biosynthesis / Q000235:genetics*; D027682:Cation Transport Proteins / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation; D012739:Gonadal Steroid Hormones / Q000008:administration & dosage; D006432:Hemochromatosis / Q000235:genetics / Q000378:metabolism; D000071020:Hemochromatosis Protein; D064451:Hepcidins / Q000096:biosynthesis / Q000235:genetics; D020249:Hormone Replacement Therapy; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D019266:Iron, Dietary / Q000633:toxicity; D035925:Iron-Regulatory Proteins / Q000096:biosynthesis* / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D009919:Orchiectomy; D009929:Organ Size; D010052:Ovariectomy; D021122:Protein Subunits; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012727:Sex Characteristics; D014158:Transcription, Genetic; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D001052:Apoferritins; D027682:Cation Transport Proteins; D058851:GPI-Linked Proteins; D012739:Gonadal Steroid Hormones; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D007501:Iron; D019266:Iron, Dietary; D035925:Iron-Regulatory Proteins; D008565:Membrane Proteins; D021122:Protein Subunits; D012333:RNA, Messenger; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2; C504414:HJV protein, mouse; C579599:Hamp protein, mouse