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Prepublished online as a Blood First Edition Paper on June 12, 2003; DOI 10.1182/blood-2003-03-0869.
Submitted March 21, 2003
Accepted May 23, 2003
Hfe deficiency increases susceptibility to cardiotoxicity and exacerbates changes in iron metabolism induced by doxorubicin
Carlos J Miranda, Hortence Makui, Ricardo J Soares, Marc Bilodeau, Jeannie Mui, Hajatollah Vali, Richard Bertrand, Nancy C Andrews, and Manuela M Santos*
CR-CHUM, Hopital Notre-Dame, Montreal, Quebec, Canada
CR-CHUM, Hopital Notre-Dame, Montreal, Quebec, Canada; UnIGENe, Instituto de Biologia Molecular e Celular, Porto, Portugal
CR-CHUM, Hopital Saint-Luc, Montreal, Quebec, Canada
Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada
Pediatrics, Howard Hughes Medical Institute, Boston, MA, USA
* Corresponding author; email: msantos{at}istar.ca.
The clinical use of doxorubicin, an anthracycline chemotherapeutic agent, is limited by cardiotoxicity. The possible involvement of iron in DOX-induced cardiotoxicity became evident from studies in which iron chelators were shown to be cardioprotective. Iron overload is found in hereditary hemochromatosis, a genetic disorder prevalent in individuals of European descent. We hypothesized that Hfe deficiency may increase susceptibility to DOX-induced toxicity. Acute cardiotoxicity and iron changes were studied after treatment with DOX in Hfe knockout (Hfe-/-) mice and wild type mice. DOX-induced iron metabolism changes were intensified in Hfe-/- mice, which accumulated significantly more iron in the heart, liver and pancreas, but less in the spleen compared to wild type mice. In addition, Hfe-deficient mice exhibited significantly greater sensitivity to DOX-induced elevations in serum creatine kinase and aspartate aminotransferase. Increased mortality after chronic DOX treatment was observed in Hfe-/- mice and Hfe+/- mice compared to wild type mice. DOX-treated Hfe-/- mice had a higher degree of mitochondrial damage and iron deposits in the heart than wild type mice. These data demonstrate that Hfe deficiency in mice increases susceptibility to DOX-induced cardiotoxicity and suggest that genetic mutations related to defects in iron metabolism may contribute to its cardiotoxicity in humans.
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