IRP1-independent alterations of cardiac iron metabolism in doxorubicin-treated mice.
Iron aggravates the cardiotoxicity of doxorubicin (DOX), a widely used anticancer anthracycline. The amount of iron in the cell is regulated by the iron regulatory proteins (IRPs)-1 and -2 that control the posttranscriptional expression of key iron metabolism genes. In vitro and cell culture studies revealed the ability of DOX to modulate the activity of both IRPs. However, conflicting data were obtained from different cell types and experimental conditions. To investigate the connection between acute DOX cardiotoxicity and the IRPs in a mammalian organism, we analyzed IRP activity and the expression of IRP target genes in the heart of mice subjected to DOX treatment. DOX exposure elicits a differential modulation of the two IRPs with reduced IRP2 activity and unchanged IRP1 activity. IRP2 downmodulation is associated with the upregulation of the ferritin L and H genes and decreased expression of the transferrin receptor 1 (TfR1). To directly test the role of IRP1 in DOX cardiotoxicity, the DOX response was analyzed in mice lacking IRP1. DOX-mediated IRP2 downmodulation and regulation of ferritin and TfR1 expression is identical in Irp1 (-/-) mice compared to wild type, as is the degree of oxidative damage of the heart assessed by thioredoxin and thiobarbituric acid reactive substance levels and by brain natriuretic peptide mRNA expression. These data demonstrate that the alterations of cardiac iron homeostasis related to acute anthracycline cardiotoxicity occur independently of IRP1. The observed IRP2 downmodulation could serve as a means to counteract DOX cardiotoxicity by reducing the "free" cellular iron pool.
Corna
Gianfranca
G
Institute of General Pathology, University of Milan, Via Mangiagalli 31, Milan 20133, Italy.
Galy
Bruno
B
Hentze
Matthias W
MW
Cairo
Gaetano
G
D000818:Animals; D004317:Doxorubicin / Q000494:pharmacology*; D005293:Ferritins / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006321:Heart / Q000187:drug effects*; D007501:Iron / Q000378:metabolism*; D035941:Iron Regulatory Protein 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*
D004317:Doxorubicin; D005293:Ferritins; D007501:Iron; D035941:Iron Regulatory Protein 1