Effects of iron loading on uptake, speciation, and chelation of iron in cultured myocardial cells.
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.
Parkes
J G
JG
Department of Clinical Biochemistry, University of Toronto, Ontario, Canada.
Hussain
R A
RA
Olivieri
N F
NF
Templeton
D M
DM
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
D007502:Iron Chelating Agents; D014168:Transferrin; D007501:Iron