Atrogin-1 ubiquitin ligase is upregulated by doxorubicin via p38-MAP kinase in cardiac myocytes
Open Access
- 17 March 2008
- journal article
- research article
- Published by Oxford University Press (OUP) in Cardiovascular Research
- Vol. 79 (1), 89-96
- https://doi.org/10.1093/cvr/cvn076
Abstract
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. 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. 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.Keywords
This publication has 25 references indexed in Scilit:
- A novel transgenic mouse model reveals deregulation of the ubiquitin‐proteasome system in the heart by doxorubicinThe FASEB Journal, 2005
- Skeletal muscle hypertrophy and atrophy signaling pathwaysThe International Journal of Biochemistry & Cell Biology, 2005
- Phosphorylation-Dependent Degradation of p300 by Doxorubicin-Activated p38 Mitogen-Activated Protein Kinase in Cardiac CellsMolecular and Cellular Biology, 2005
- N-cadherin-mediated cell adhesion determines the plasticity for cell alignment in response to mechanical stretch in cultured cardiomyocytesBiochemical and Biophysical Research Communications, 2004
- The IGF-1/PI3K/Akt Pathway Prevents Expression of Muscle Atrophy-Induced Ubiquitin Ligases by Inhibiting FOXO Transcription FactorsMolecular Cell, 2004
- Foxo Transcription Factors Induce the Atrophy-Related Ubiquitin Ligase Atrogin-1 and Cause Skeletal Muscle AtrophyCell, 2004
- Akt Down-regulation of p38 Signaling Provides a Novel Mechanism of Vascular Endothelial Growth Factor-mediated Cytoprotection in Endothelial CellsJournal of Biological Chemistry, 2001
- Cardioprotective Effects of a Novel Proteasome Inhibitor Following Ischemia and Reperfusion in the Isolated Perfused Rat HeartJournal of Molecular and Cellular Cardiology, 1999
- THE UBIQUITIN SYSTEMAnnual Review of Biochemistry, 1998
- Cloning and Characterization of Three Human Forkhead Genes That Comprise an FKHR-like Gene SubfamilyGenomics, 1998