Peroxisome proliferator-activated receptor delta (PPARdelta) activation protects H9c2 cardiomyoblasts from oxidative stress-induced apoptosis.
OBJECTIVE
Activation of peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARgamma plays beneficial roles in cardiovascular disorders such as atherosclerosis and heart reperfusion. Although PPARalpha and gamma have been documented to reduce oxidative stress in the vasculature and the heart, the role of PPARdelta remains poorly studied.


RESULTS
We focused on PPARdelta 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 PPARdelta is the predominantly expressed isotype whereas PPARalpha was weakly detected. By performing cell viability assays, we also showed that the selective PPARdelta agonist GW501516 protected cells from H(2)O(2)-induced cell death. The protective effect of GW501516 was due to an inhibition of H(2)O(2)-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 PPARdelta that the protection induced by GW501516 was totally dependent on PPARdelta. Semi-quantitative RT-PCR and Western blotting analysis demonstrated that GW501516 treatment upregulated catalase. Moreover, forced overexpression of catalase inhibited H(2)O(2)-triggered apoptosis, as evidenced by annexin-V labeling.


CONCLUSIONS
Taken together, our results account for an important role of PPARdelta in inhibiting the onset of oxidative stress-induced apoptosis in H9c2 cells. PPARdelta appears to be a new therapeutic target for the regulation of heart reperfusion-associated oxidative stress and stimulation of enzymatic antioxidative defences.
Pesant
Matthieu
M
Laboratoire de Physiopathologie et Pharmacologie Cardiovasculaires Expérimentales, Biologie Animale Cellulaire et Moléculaire, Faculté des Sciences Gabriel, Université de Bourgogne, IFR Santé 100, 6 Boulevard Gabriel, 21000 Dijon, France.
Sueur
Stéphanie
S
Dutartre
Patrick
P
Tallandier
Mireille
M
Grimaldi
Paul A
PA
Rochette
Luc
L
Connat
Jean-Louis
JL
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western / Q000379:methods; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002460:Cell Line; D053938:DNA Fragmentation; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D032386:Myoblasts, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D018384:Oxidative Stress; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology*; D014162:Transfection; D015854:Up-Regulation
C425931:GW 501516; D047494:PPAR delta; D013844:Thiazoles; D006861:Hydrogen Peroxide; D002374:Catalase; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases