Cardiovascular Research Advance Access originally published online on March 17, 2008
Cardiovascular Research 2008 79(1):89-96; doi:10.1093/cvr/cvn076
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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, Osaka565-0871, Japan
* Corresponding author. Tel: +81 6 6879 8258; fax: +81 6 6879 8259. E-mail address: azuma{at}phs.osaka-u.ac.jp
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.
KEYWORDS Atrophy; Ubiquitin-proteasome system; Mitogen-activated protein kinase; Cardiac myocyte
Time for primary review: 26 days
The first two authors equally contributed to this study.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Welle, K. Burgess, C. A. Thornton, and R. Tawil Relation between extent of myostatin depletion and muscle growth in mature mice Am J Physiol Endocrinol Metab, October 1, 2009; 297(4): E935 - E940. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Su and X. Wang The ubiquitin-proteasome system in cardiac proteinopathy: a quality control perspective Cardiovasc Res, September 16, 2009; (2009) cvp287v2. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Li, J. S. Moylan, M. A. Chambers, J. Smith, and M. B. Reid Interleukin-1 stimulates catabolism in C2C12 myotubes Am J Physiol Cell Physiol, January 1, 2009; 297(3): C706 - C714. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Kim, R. R. Roy, J. A. Kim, H. Zhong, F. Haddad, K. M. Baldwin, and V. R. Edgerton Gene expression during inactivity-induced muscle atrophy: effects of brief bouts of a forceful contraction countermeasure J Appl Physiol, October 1, 2008; 105(4): 1246 - 1254. [Abstract] [Full Text] [PDF]
|
|