Genes encoding enzymes involved in fatty acids (FA) and glucose oxidation are transcriptionally regulated by peroxisome proliferator-activated receptors (PPAR), members of the nuclear receptor superfamily. Under conditions associated with O 2 deficiency, PPAR-α modulates substrate switch (between FA and glucose) aimed at the adequate energy production to maintain basic cardiac function. Both, positive and negative effects of PPAR-α activation on myoc ardial ischemia/reperfusion (I/R) injury have been reported. Moreover, the role of PPAR-mediated metabolic shifts in cardioprotective mechanisms of preconditioning (PC) is relatively less investigated. We explored the effects of PPAR-α upregulation mimicking a delayed “second window” of PC on I/R injury in the rat heart and potential downstream mechanisms involved. Pretreatment of rats with PPAR-α agonist WY-14643 (WY, 1 mg/kg, i.p.) 24 h prior to I/R reduced post-ischemic stunning, arrhythmias and the extent of lethal injury (infarct size) and ap optosis (caspase-3 expression) in isolated hearts exposed to 30-min global ischemia and 2-h reperfusion. Protection was associated with remarkably increased expression of PPAR- α target genes promoting FA utilization (medium-chain acyl-CoA de hydrogenase, pyruvate dehydrogenase kinase-4 and carnitine palmitoyltransferase I) and reduced expression of glucose transporter GLUT-4 responsible for glucose transport and metabolism. In addition, enhanced Akt phosphorylation and protein levels of eNOS, in conjunction with blunting of cardioprotection by NOS inhibitor L-NAME, were observed in the WY-treated hearts. Conclusions: upregulation of PPAR-α target metabolic genes involved in FA oxidation may underlie a delayed phase PC-like protection in the rat heart. Potential non-genomic effects of PPAR-α-mediated cardioprotection may involve activation of prosurvival PI3K/Akt pathway and its downstream targets such as eNOS and subsequently reduced apoptosis., T. Ravingerová ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy