title: 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.
abstract: 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 PPARβ/δ under the setting of oxidative stress induced by H2O2 in adult rat cardiac myocytes. The selective PPARβ/δ 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 PPARβ/δ agonist. These effects were abolished in the presence of the PPARβ/δ antagonist indicating that the effect was through PPARβ/δ receptor activation. Treatment with PPARβ/δ 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 PPARβ/δ inhibited the oxidative-stress-induced MMP-2 and MMP-9 mRNA upregulation. It is concluded that PPARβ/δ 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.
authors.affiliation: Laboratory of Animal Physiology, School of Biology, Aristotle University of Thessaloniki, Greece.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Barlaka
authors.affiliation: Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Hungary; Pharmahungary Group, Szeged, Hungary.
authors.forename: Anikó
authors.initials: A
authors.lastname: Görbe
authors.affiliation: Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Hungary.
authors.forename: Renáta
authors.initials: R
authors.lastname: Gáspár
authors.affiliation: Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Hungary.
authors.forename: János
authors.initials: J
authors.lastname: Pálóczi
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary; Pharmahungary Group, Szeged, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Ferdinandy
authors.affiliation: Laboratory of Animal Physiology, School of Biology, Aristotle University of Thessaloniki, Greece. Electronic address: lazou@bio.auth.gr.
authors.forename: Antigone
authors.initials: A
authors.lastname: Lazou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D047494:PPAR delta / Q000819:agonists* / Q000037:antagonists & inhibitors; D048068:PPAR-beta / Q000819:agonists* / Q000037:antagonists & inhibitors; D017208:Rats, Wistar; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D006861:Hydrogen Peroxide; D020782:Matrix Metalloproteinases; D047494:PPAR delta; D048068:PPAR-beta; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D013450:Sulfones; D013844:Thiazoles; D013876:Thiophenes; C529769:GSK0660; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds
keywords: Apoptosis; Bcl-2; Cardiac myocytes; Caspase 3; GSK0660 (PubChem CID: 46233311); GW0742 (PubChem CID: 9934458); Hydrogen peroxide (PubChem CID: 784); Matrix metalloproteinases; Oxidative stress; PPARβ/δ