Hfe deficiency increases susceptibility to cardiotoxicity and exacerbates changes in iron metabolism induced by doxorubicin

• Type: Article in International Scientific Journal
• Date: 2003

Authors

Miranda, CJ (Author) Other; Makui, H (Author) Other; Soares, RJ (Author) Other; Bilodeau, M (Author) Other; Mui, J (Author) Other; Vali, H (Author) Other; Bertrand, R (Author) Other; Andrews, NC (Author) Other; Santos, MM (Author) REIT

Journal

Title: Blood

Vol. 102

Pages: 2574-2580

ISSN: 0006-4971

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 142 Citations

Other information

Authenticus ID: P-000-EWH

DOI: 10.1182/blood-2003-03-0869

Abstract (EN): The clinical use of doxorubicin (DOX), 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 knock-out (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 with 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 with wild-type mice. DOX-treated Hfe(-/-) mice had a higher degree of mitochondrial damage and iron deposits in the heart than did 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. (C) 2003 by The American Society of Hematology.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 7