Abstract
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 erythroid 2-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 cardiac performance. Furthermore, although LV oxidized glutathione content was increased, the oxidized-to-reduced glutathione 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 manganese superoxide dismutase and NAD(P)H dehydrogenase [quinone] 1 were observed together with heme oxygenase 1 up-regulation. Although 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 the expression of mitochondrial genes. These results imply that global oxidative stress need not be a factor responsible for the development of anthracycline-induced HF, whereas suppression of mitochondrial biogenesis might be involved.
Footnotes
This study was supported by the Czech Science Foundation [Grant 305/09/0416]; Charles University [Grant SVV 264901/2012 and the program PRVOUK P37/5].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
ABBREVIATIONS:
- ANT
- anthracycline
- ANOVA
- analysis of variance
- ARE
- antioxidant response element
- COX
- cytochrome c oxidase
- CTR
- control
- CuZnSOD
- copper zinc superoxide dismutase
- DAU
- daunorubicin
- DTT
- dithiothreitol
- FS
- fractional shortening
- FU
- follow-up
- GCLC
- glutamate-cysteine ligase catalytic subunit
- GPx
- glutathione peroxidase
- GR
- glutathione reductase
- GSH
- reduced glutathione
- GSSG
- oxidized glutathione
- GST
- glutathione transferase
- HO1
- heme oxygenase 1
- HPLC
- high-performance liquid chromatography
- LMV
- last measured value
- LV
- left ventricular
- LVEDD
- LV end-diastolic diameter
- MDA
- malondialdehyde
- MnSOD
- manganese superoxide dismutase
- mtDNA
- mitochondrial DNA
- nDNA
- nuclear DNA
- NQO1
- NAD(P)H dehydrogenase [quinone] 1
- NRF1
- nuclear respiratory factor 1
- Nrf2
- nuclear factor erythroid 2-related factor 2
- PCR
- polymerase chain reaction
- qPCR
- quantitative PCR
- PGC1α
- peroxisome proliferator-activated receptor γ coactivator 1α
- ROS
- reactive oxygen species
- smtCK
- sarcomeric mitochondrial creatine kinase
- TFAM
- mitochondrial transcription factor A.
- Received July 11, 2012.
- Accepted August 21, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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