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

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.