Dystrophin-deficiency increases the susceptibility to doxorubicin-induced cardiotoxicity.
OBJECTIVE
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.
Deng
Shiwei
S
Department of Pharmacology, Johannes Gutenberg University, 55101 Mainz, Germany.
Kulle
Bettina
B
Hosseini
Mehdi
M
Schlüter
Gregor
G
Hasenfuss
Gerd
G
Wojnowski
Leszek
L
Schmidt
Albrecht
A
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D018450:Disease Progression; D004198:Disease Susceptibility; D004317:Doxorubicin / Q000009:adverse effects*; D016189:Dystrophin / Q000172:deficiency*; D005260:Female; D015870:Gene Expression; D014644:Genetic Variation; D006331:Heart Diseases / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000235:genetics; D051379:Mice; D046228:Microarray Analysis; D012307:Risk Factors; D014463:Ultrasonography
D000903:Antibiotics, Antineoplastic; D016189:Dystrophin; D004317:Doxorubicin