© 2007 European Society of Cardiology
Dystrophin-deficiency increases the susceptibility to doxorubicin-induced cardiotoxicity
a Department of Pharmacology, Johannes Gutenberg University 55101 Mainz, Germany
b Department of Biostatistics and Department of Mathematics, University of Oslo Norway
c Department of Human Genetics, University of Göttingen 37075 Göttingen, Germany
d Department of Cardiology and Pneumology, University of Göttingen 37075 Gottingen, Germany
* Corresponding author. Department of Pharmacology, Johannes Gutenberg University Obere Zahlbacher Strasse 67, 55101 Mainz, Germany. Tel.: +49 6131 3933460; fax: +49 941 5992 36727. E-mail address: wojnowski{at}uni-mainz.de (L. Wojnowski).
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Abstract |
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Background and aim: The clinical use of doxorubicin (DOX) and other anthracyclines is limited by a dosage-dependent cardiotoxicity, which can lead to cardiomyopathy. The role of the individual genetic makeup in this disorder is poorly understood. Alterations in genes encoding cardiac cytoskeleton or sarcolemma proteins may increase the susceptibility to doxorubicin-related cardiotoxicity.
Methods: Female dystrophin-deficient mice (MDX) and age-matched wild-type mice underwent chronic treatment with doxorubicin. Cardiac function and tissue damage were assessed by echocardiography and histopathology, respectively. Gene expression changes were investigated using microarrays.
Results: DOX treatment resulted in mortality, cardiac insufficiency, and cardiac interstitial fibrosis. These alterations were more pronounced in DOX-treated MDX mice than in DOX-treated wild-type mice. Changes in gene expression were more numerous in MDX mice, including genes involved in cell adhesion, oxidative stress, cytoskeleton organization, inflammatory and immune response and cell death.
Conclusions: Dystrophin deficiency facilitates the development and progression of doxorubicin-induced cardiac injury. The underlying mechanisms may involve changes in cell adhesion, in cytoskeleton, as well as in inflammatory and immune responses. Genetic variants of cytoskeletal proteins in humans may affect the individual susceptibility to doxorubicin. Cardiotoxic drugs may accelerate the manifestation of pre-clinical cardiomyopathies caused by deficiencies in cytoskeletal or sarcolemma proteins.
Key Words: Doxorubicin • Dystrophin • Cardiotoxicity
Received December 22, 2006; Revised June 15, 2007; Accepted July 17, 2007
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