title: Effects of iron loading on uptake, speciation, and chelation of iron in cultured myocardial cells.
abstract: Accumulation of Fe in the myocardium in circumstances of transferrin saturation is associated with heart failure in Fe-loaded patients. To characterize the underlying causes of this phenomenon, we measured the flux as well as the speciation of Fe in normal and Fe-loaded cultures of rat myocardiocytes. Fe loading with low-molecular-weight Fe (ferric ammonium citrate) promoted a dose- and time-dependent increase in the rate of uptake of non-transferrin-bound Fe (NTBI) that was positively correlated (R = 0.9, p < 0.005) with cellular iron content. At concentrations sufficient to produce this up-regulation, membrane integrity was unaffected but the rate of spontaneous beating of the cells was decreased by 60%. The enhanced rate of NTBI uptake in Fe-loaded cells reverted to control rates after treatment with therapeutic concentrations of Fe chelators deferoxamine, 1,2-dimethyl-3-hydroxypyrid-4-one and 1,2-diethyl-3-hydroxypyrid-4-one under conditions where approximately 80% of the cellular Fe was removed by chelation. Fe loading of cultured myocytes also induced shifts in Fe speciation. Thus the ratio of Fe bound in hemosiderin-like precipitates to ferritin-bound Fe increased twofold, from a range of 0.84 to 1.44 in control cells to 1.96 to 3.3 in iron-loaded cells. This increased ratio was similar to that measured in the heart and liver of a thalassemic patient who underwent a double transplant for the failure of both organs, even though the Fe content of the heart (mean, 5.8 mg Fe/gm dry weight) was much less than that of the liver (28.1 mg/gm dry weight). These results suggest that increased rates of uptake of NTBI may exacerbate iron loading of the heart and contribute to iron-mediated cardiotoxicity, whereas the clinical benefits of chelation therapy may be enhanced by the down-regulation of NTBI uptake.
authors.affiliation: Department of Clinical Biochemistry, University of Toronto, Ontario, Canada.
authors.forename: J G
authors.initials: JG
authors.lastname: Parkes
authors.forename: R A
authors.initials: RA
authors.lastname: Hussain
authors.forename: N F
authors.initials: NF
authors.lastname: Olivieri
authors.forename: D M
authors.initials: DM
authors.lastname: Templeton
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001692:Biological Transport; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D066298:In Vitro Techniques; D007501:Iron / Q000378:metabolism* / Q000633:toxicity; D007502:Iron Chelating Agents / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D014168:Transferrin / Q000378:metabolism
chemical_list: D007502:Iron Chelating Agents; D014168:Transferrin; D007501:Iron