Atrogin-1 ubiquitin ligase is upregulated by doxorubicin via p38-MAP kinase in cardiac myocytes

• Published in: Cardiovascular research Vol. 79; no. 1; pp. 89 - 96
• Main Authors: Yamamoto, Yasuhiro, Hoshino, Yuki, Ito, Takashi, Nariai, Tetsuro, Mohri, Tomomi, Obana, Masanori, Hayata, Nozomi, Uozumi, Yoriko, Maeda, Makiko, Fujio, Yasushi, Azuma, Junichi
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.07.2008
• Subjects: Adenoviridae - genetics; Animals; Antibiotics, Antineoplastic - adverse effects; Antibiotics, Antineoplastic - pharmacology; Atrophy; Biological and medical sciences; Cardiac myocyte; Cardiology. Vascular system; Cardiomyopathies - chemically induced; Cells, Cultured; Doxorubicin - adverse effects; Doxorubicin - pharmacology; Gene Transfer Techniques; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mitogen-activated protein kinase; Muscle Proteins - drug effects; Muscle Proteins - genetics; Muscle Proteins - metabolism; Myocytes, Cardiac - enzymology; Myocytes, Cardiac - pathology; p38 Mitogen-Activated Protein Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Wistar; Signal Transduction - drug effects; SKP Cullin F-Box Protein Ligases - drug effects; SKP Cullin F-Box Protein Ligases - genetics; SKP Cullin F-Box Protein Ligases - metabolism; Ubiquitin-proteasome system; Up-Regulation - drug effects; Atrophy; Mitogen-activated protein kinase; Cardiac myocyte; Ubiquitin-proteasome system; Heart; Multicatalytic endopeptidase complex; Enzyme; Transferases; Doxorubicin; Phlebology; System; Myocyte; Peptidases; Ligases; Hydrolases; Circulatory system; Cardiology
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvn076

Aims Doxorubicin (DOX) is one of the most effective anti-neoplastic agents; however, its clinical use is limited by 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 ligases, in DOX-induced cardiotoxicity. Methods and results This method involved intraperitoneal administration of DOX-induced atrogin-1 in the hearts and skeletal muscles of 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 (caAkt), 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 caAkt 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.