Key result
PPAR-delta agonist GW0742 reverses doxorubicin-induced systolic and diastolic cardiac dysfunction in rats.
Activation of PPAR-delta by GW0742 mitigates doxorubicin-induced cardiotoxicity and restores cardiac performance in a rat model, suggesting a potential future therapeutic mechanism.
The present study investigates the changes of peroxisome proliferator-activated receptors δ (PPAR δ ) expression and troponin phosphorylation in heart of rats which were treated with doxorubicin (DOX). Wistar rats which were treated with DOX according to a previous method. The protein levels of PPAR δ and troponin phosphorylation were measured using Western blot. The PPAR δ expression in heart was markedly reduced in DOX-treated rats showing a marked decrease in cardiac dP/dT and cardiac output. Also, cardiac troponin phosphorylation was lowered in DOX-treated rats. Meanwhile, combined treatment with the agonist of PPAR δ (GW0742) reversed the decrease of cardiac dP/dT and cardiac output in DOX-treated rats. Then, primary cultured cardiomyocytes from neonatal rats were used to measure the changes of calcium concentration in cells. In addition to both decrease of PPAR δ expression and troponin phosphorylation in neonatal cardiomyocytes by DOX, a marked decrease of calcium concentration was also observed. Our results suggest the mediation of cardiac PPAR δ in DOX-induced cardiotoxicity in rats. Thus, activation of PPAR δ may restore the expression of p-TnI and the cardiac performance in DOX-induced cardio toxicity in rats.
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Chen et al. (2013) studied Doxorubicin-induced cardiotoxicity. GW0742 (PPAR delta agonist) vs. Vehicle was evaluated on Cardiac output and dP/dt (p=<0.001). The PPAR-delta agonist GW0742 significantly reversed the doxorubicin-induced decreases in cardiac output, max dP/dt, min dP/dt, and cardiac troponin I phosphorylation in rats.
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