Peroxisome proliferator-activated receptor δ (PPARδ) activation protects H9c2 cardiomyoblasts from oxidative stress-induced apoptosis

Objective: Activation of peroxisome proliferator-activated receptor alpha (PPAR alpha) and PPAR gamma plays beneficial roles in cardiovascular disorders such as atherosclerosis and heart reperfusion. Although PPAR alpha and gamma have been documented to reduce oxidative stress in the vasculature and the heart, the role of PPAR delta remains poorly studied. Methods and results: We focused on PPAR delta function in the regulation of oxidative stress-induced apoptosis in the rat cardiomyoblast cell line H9c2. Using semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), we showed that PPAR delta is the predominantly expressed isotype whereas PPAR alpha was weakly detected. By performing cell viability assays, we also showed that the selective PPAR delta agonist GW501516 protected cells from H2O2-induced cell death. The protective effect of GW501516 was due to an inhibition of H2O2-triggered apoptosis as shown by annexin-V labeling, DNA fragmentation analysis, and caspase-3 activity measurement. We demonstrated by transient transfection of a dominant negative mutant of PPAR delta that the protection induced by GW501516 was totally dependent on PPAR delta. Semi-quantitative RT-PCR and Western blotting analysis demonstrated that GW501516 treatment upregulated catalase. Moreover, forced overexpression of catalase inhibited H2O2-triggered apoptosis, as evidenced by annexin-V labeling. Conclusion: Taken together, our results account for an important role of PPAR delta in inhibiting the onset of oxidative stress-induced apoptosis in H9c2 cells. PPAR delta appears to be a new therapeutic target for the regulation of heart reperfusion-associated oxidative stress and stimulation of enzymatic antioxidative defences. (C) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.