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Chronic anthracycline cardiotoxicity: molecular and functional analysis with focus on Nrf2 and mitochondrial biogenesis pathways.
MedLine Citation:
PMID:  22915767     Owner:  NLM     Status:  Publisher    
Anthracycline anticancer drugs (e.g., doxorubicin or daunorubicin) can induce chronic cardiotoxicity and heart failure (HF), both of which are believed to be based on oxidative injury and mitochondrial damage. In this study, molecular and functional changes induced by chronic anthracycline treatment with progression into HF in post-treatment follow up were analyzed with special emphasis on nuclear factor-E2-related factor 2 (Nrf2) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) pathways. Chronic cardiotoxicity was induced in rabbits with daunorubicin (3 mg/kg, weekly for 10 weeks) and the animals were followed for another 10 weeks. Echocardiography revealed a significant drop in left ventricular (LV) systolic function during the treatment with marked progression to LV dilation and congestive HF in the follow up. Although daunorubicin-induced LV lipoperoxidation was found, it was only loosely associated with the cardiac performance. Furthermore, although LV GSSG content was increased, the GSSG/GSH ratio itself remained unchanged. Neither Nrf2, the master regulator of antioxidant response, nor the majority of its target genes showed up-regulation in the study. However, down-regulation of MnSOD and NQO1 were observed together with HO1 up-regulation. While marked perturbations in mitochondrial functions were found, no induction of PGC1α-controlled mitochondrial biogenesis pathway was revealed. Instead, especially in the post-treatment period, an impaired regulation of this pathway was observed along with down-regulation of expression of mitochondrial genes. These results imply that global oxidative stress need not be an executive factor responsible for development of anthracycline-induced HF, while suppression of mitochondrial biogenesis might be involved in this matter.
Eduard Jirkovsky; Olga Popelova; Pavla Krivakova-Stankova; Anna Vavrova; Milos Hroch; Pavlina Haskova; Eva Brcakova-Dolezelova; Stanislav Micuda; Michaela Adamcova; Tomas Simunek; Zuzana Cervinkova; Vladimir Gersl; Martin Sterba
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-8-22
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  -     ISSN:  1521-0103     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-8-23     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
1 Charles University in Prague, Faculty of Medicine in Hradec Kralove;
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