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Peroxisome Proliferator-Activated Receptor-α Inhibition Protects Against Doxorubicin-Induced Cardiotoxicity in Mice

Abstract

Doxorubicin is an effective chemotherapeutic drug against a considerable number of malignancies. However, its toxic effects on myocardium are confirmed as major limit of utilization. PPAR-α is highly expressed in the heart, and its activation leads to an increased cardiac fatty acid oxidation and cardiomyocyte necrosis. This study was performed to adjust the hypothesis that PPAR-α receptor inhibition protects against doxorubicin-induced cardiac dysfunction in mice. Male Balb/c mice were used in this study. Left atria were isolated, and their contractility was measured in response to electrical field stimulation in a standard organ bath. PPAR-α activity was measured using specific PPAR-α antibody in an ELISA-based system coated with double-strand DNA containing PPAR-α response element sequence. Moreover, cardiac MDA and TNF-α levels were measured by ELISA method. Following incubation with doxorubicin (35 µM), a significant reduction in atrial contractility was observed (P < 0.001). Pretreatment of animals with a selective PPAR-α antagonist, GW6471, significantly improved doxorubicin-induced atrial dysfunction (P < 0.001). Furthermore, pretreatment of the mice with a non-selective cannabinoid agonist, WIN55212-2, significantly decreased PPAR-α activity in cardiac tissue, subsequently leading to significant improvement in doxorubicin-induced atrial dysfunction (P < 0.001). Also, GW6471 and WIN significantly reduced cardiac MDA and TNF-α levels compared with animals receiving doxorubicin (P < 0.001). The study showed that inhibition of PPAR-α is associated with protection against doxorubicin-induced cardiotoxicity in mice, and cannabinoids can potentiate the protection by PPAR-α blockade. Moreover, PPAR-α may be considered as a target to prevent cardiotoxicity induced by doxorubicin in patients undergoing chemotherapy.

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Abbreviations

PPAR-α:

Peroxisome proliferator-activated receptor-α

DOX:

Doxorubicin

MDA:

Malondialdehyde

TNF-α:

Tumor necrosis factor-α

WIN:

WIN55212-2

ELISA:

Enzyme-linked immunosorbent assay

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Acknowledgments

This study was supported by grants from Dean of Research, Tehran University of Medical Sciences. The authors would like to thank Miss Maryam Rahimi Balai and Dr Alireza Mani for cooperation during conduct of the study.

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Authors declare no conflict of interest.

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Correspondence to Ahmad Reza Dehpour.

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Rahmatollahi, M., Baram, S.M., Rahimian, R. et al. Peroxisome Proliferator-Activated Receptor-α Inhibition Protects Against Doxorubicin-Induced Cardiotoxicity in Mice. Cardiovasc Toxicol 16, 244–250 (2016). https://doi.org/10.1007/s12012-015-9332-0

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  • DOI: https://doi.org/10.1007/s12012-015-9332-0

Keywords

  • Peroxisome proliferator-activated receptor-α
  • Cannabinoids
  • Doxorubicin
  • Cardiotoxicity