Activation of PPARβ/δ protects cardiac myocytes from oxidative stress-induced apoptosis by suppressing generation of reactive oxygen/nitrogen species and expression of matrix metalloproteinases

Heart failure still remains one of the leading causes of morbidity and mortality worldwide. A major contributing factor is reactive oxygen/nitrogen species (RONS) overproduction which is associated with cardiac remodeling partly through cardiomyocyte apoptosis. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear receptor superfamily and have been implicated in cardioprotection. However, the molecular mechanisms are largely unexplored. In this study we sought to investigate the potential beneficial effects evoked by activation of PPAR beta/delta under the setting of oxidative stress induced by H2O2 in adult rat cardiac myocytes. The selective PPAR beta/delta agonist GW0742 inhibited the H2O2-induced apoptosis and increased cell viability. In addition, generation of RONS was attenuated in cardiac myocytes in the presence of PPAR beta/delta agonist. These effects were abolished in the presence of the PPAR beta/delta antagonist indicating that the effect was through PPAR beta/delta receptor activation. Treatment with PPAR beta/delta agonist was also associated with attenuation of caspase-3 and PARP cleavage, upregulation of anti-apoptotic Bcl-2 and concomitant downregulation of pro-apoptotic Bax. In addition, activation of PPAR beta/delta inhibited the oxidative-stress-induced MMP-2 and MMP-9 mRNA upregulation. It is concluded that PPAR beta/delta activation exerts a cytoprotective effect in adult rat cardiac myocytes subjected to oxidative stress via inhibition of oxidative stress, MMP expression, and apoptosis. Our data suggest that the novel connection between PPAR signaling and MMP down-regulation in cardiac myocytes might represent a new target for the management of oxidative stress-induced cardiac dysfunction. (C) 2015 Elsevier Ltd. All rights reserved.