title: Delayed cardioprotective effects of WY-14643 are associated with inhibition of MMP-2 and modulation of Bcl-2 family proteins through PPAR-α activation in rat hearts subjected to global ischaemia-reperfusion.
abstract: Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors regulating cardiac lipid metabolism and energy homeostasis. Although the activation of PPARs has been implicated in cardioprotection, the molecular mechanisms are largely unexplored. In this study, we aimed to investigate the effect of the PPAR-α agonist WY-14643 (WY), mimicking a delayed effect of preconditioning in rat hearts exposed to acute ischaemia-reperfusion (I/R) 24 h later, and to define whether antioxidative and antiapoptotic mechanisms are involved. Treatment with WY markedly attenuated post-ischaemic contractile dysfunction (as evidenced by the reduced infarct size), the higher left ventricular developed pressure (LVDP) recovery, and the decreased occurrence of arrhythmias. These effects were abolished in the presence of the PPAR-α antagonist MK886. Heme oxygenase-1, a key antioxidative enzyme implicated in cytoprotection, was upregulated in response to WY at baseline, but was markedly reduced after I/R, indicating reduced oxidative stress. WY treatment was also associated with decreased mRNA levels and enzymatic activity of matrix metalloproteinase-2, and increased ratios of Bcl-2:Bax proteins. These results indicate that PPAR-α activation by its selective ligand WY may confer delayed preconditioning-like protection in rat hearts subjected to I/R by modulating oxidative stress, activation of matrix metalloproteinase-2, and expression of Bcl-2 and Bax.
authors.affiliation: School of Biology, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Barlaka
authors.forename: Veronika
authors.initials: V
authors.lastname: Ledvényiová
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Galatou
authors.forename: Miroslav
authors.initials: M
authors.lastname: Ferko
authors.forename: Slávka
authors.initials: S
authors.lastname: Čarnická
authors.forename: Táňa
authors.initials: T
authors.lastname: Ravingerová
authors.forename: Antigone
authors.initials: A
authors.lastname: Lazou
mesh_terms: D000818:Animals; D006334:Heart Function Tests; D066298:In Vitro Techniques; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D047493:PPAR alpha / Q000819:agonists*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D047493:PPAR alpha; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; C006253:pirinixic acid; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat