Cardiovascular Research Advance Access [Accepted Manuscript] published online on March 17, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn076
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Atrogin-1 ubiquitin ligase is upregulated by doxorubicin via p38-MAP kinase in cardiac myocytes
Department of Clinical Pharmacology and Pharmacogenomics Graduate School of Pharmaceutical Sciences Osaka University 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan
All correspondence should be addressed to J. Azuma Tel: +81-6-6879-8258. Fax: +81-6-6879-8259 (azuma{at}phs.osaka-u.ac.jp)
Aim: Doxorubicin (DOX) is one of the most effective anti-neoplastic agents; however, its clinical use is limited by the drug-induced cardiomyopathy. The molecular mechanisms responsible for this toxicity remain to be fully addressed. In the present study, we investigated the involvement of atrogin-1, one of the muscle-specific ubiquitin ligase, in DOX-induced cardiotoxicity.
Methods and results: Intraperitoneal administration of DOX induced atrogin-1 in the hearts and skeletal muscles in C57BL/6 mice. Consistently, atrogin-1 mRNA was upregulated with DOX treatment in cultured rat neonatal cardiomyocytes. Adenoviral transfer of atrogin-1 induced a reduction in cell size that was ameliorated by the ubiquitin proteasome inhibitor MG-132. The transduction of constitutively active Akt, a serine/threonine protein kinase, inhibited the DOX-mediated induction of atrogin-1. The phosphorylation status of Akt and its downstream target, FOXO, was not affected by DOX. DOX treatment did not activate the atrogin-1 promoter that contains FOXO-binding sites, suggesting that DOX induced atrogin-1 without modulating the Akt/FOXO pathway. Importantly, DOX activated p38-mitogen activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK). Furthermore, pharmacological inhibition of p38-MAPK, but not JNK, abrogated DOX-mediated induction of atrogin-1. Finally, adenoviral transfer of constitutively active Akt inhibited the DOX-induced p38-MAPK activation.
Conclusions: DOX induces atrogin-1 through a p38-MAPK-dependent pathway in cardiac myocytes. Constitutive activation of Akt negatively regulates DOX-mediated atrogin-1 induction by inhibiting p38-MAPK activity as a novel mechanism.
Time for primary review: 26 days
* These two equally contributed to this study.
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