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Cardiovascular Research 2006 69(2):440-449; doi:10.1016/j.cardiores.2005.10.019
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Copyright © 2005, European Society of Cardiology

Peroxisome proliferator-activated receptor {delta} (PPAR{delta}) activation protects H9c2 cardiomyoblasts from oxidative stress-induced apoptosis

Matthieu Pesanta, Stéphanie Sueura, Patrick Dutartreb,1, Mireille Tallandierb, Paul A. Grimaldic, Luc Rochettea and Jean-Louis Connata,*

aLaboratoire de Physiopathologie et Pharmacologie Cardiovasculaires Expérimentales, Biologie Animale Cellulaire et Moléculaire, Faculté des Sciences Gabriel, Université de Bourgogne, IFR Santé 100, 6 Bd Gabriel, 21000 Dijon, France
bLaboratoires Fournier Pharma, Biologie Exploratoire, 50 rue de Dijon, 21121 Daix, France
cCentre de Biochimie, INSERM U636, UFR Sciences, Parc Valrose, 06108-Nice cedex, France

* Corresponding author. Tel.: +33 380 39 62 16; fax: +33 380 39 38 25. Email address: jean-louis.connat{at}u-bourgogne.fr

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.

KEYWORDS Nuclear receptors; Hydrogen peroxide; Cell death; Catalase; PPAR{delta}; Dominant negative mutant; Peroxisome proliferator-activated receptor {delta}

1 Present affiliation: Laboratoire de Biologie Moléculaire et Cellulaire, Université de Bourgogne, 6 Bd Gabriel, 21000 Dijon, France.

Time for primary review 21 days


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