Abstract
Doxorubicin is believed to cause dose-dependent cardiotoxicity through redox cycling and the generation of reactive oxygen species (ROS). Here we show that cardiomyocyte-specific deletion of Top2b (encoding topoisomerase-IIβ) protects cardiomyocytes from doxorubicin-induced DNA double-strand breaks and transcriptome changes that are responsible for defective mitochondrial biogenesis and ROS formation. Furthermore, cardiomyocyte-specific deletion of Top2b protects mice from the development of doxorubicin-induced progressive heart failure, suggesting that doxorubicin-induced cardiotoxicity is mediated by topoisomerase-IIβ in cardiomyocytes.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects
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Cardiotoxins*
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DNA Topoisomerases, Type II / genetics
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DNA-Binding Proteins / genetics
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Doxorubicin / toxicity*
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Heart Failure / chemically induced
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Humans
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Mice
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Mitochondrial Turnover / drug effects*
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Myocytes, Cardiac* / drug effects
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Myocytes, Cardiac* / metabolism
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Myocytes, Cardiac* / pathology
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Poly-ADP-Ribose Binding Proteins
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Reactive Oxygen Species / metabolism
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Sequence Deletion
Substances
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Cardiotoxins
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DNA-Binding Proteins
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Poly-ADP-Ribose Binding Proteins
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Reactive Oxygen Species
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Doxorubicin
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DNA Topoisomerases, Type II
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TOP2B protein, human
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Top2b protein, mouse