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PPAR-αlpha activation as a preconditioning-like intervention in rats in vivo confers myocardial protection against acute ischaemia-reperfusion injury: Involvement of PI3K-Akt


ΤίτλοςPPAR-αlpha activation as a preconditioning-like intervention in rats in vivo confers myocardial protection against acute ischaemia-reperfusion injury: Involvement of PI3K-Akt
Publication TypeJournal Article
Year of Publication2012
AuthorsRavingerová T, Čarnická S, Nemčeková M, Ledvényiová V, Adameová A, Kelly T, Barlaka E, Galatou E, Khandelwal VKM, Lazou A
JournalCanadian journal of physiology and pharmacology
Volume90
Pagination1135-1144
ISBN Number00084212
Λέξεις κλειδιάanimal tissue, article, Cardioprotection, controlled study, drug effect, drug mechanism, enzyme phosphorylation, gene expression regulation, heart infarction prevention, heart infarction size, heart muscle ischemia, heart protection, heart ventricle fibrillation, isolated heart, male, Metabolic genes, Myocardial ischaemia-reperfusion, nonhuman, peroxisome proliferator activated receptor alpha, phosphatidylinositol 3 kinase, PI3K-Akt, pirinixic acid, PPAR-α activation, priority journal, protein kinase B, rat, reperfusion injury, upregulation, WY-14643
Abstract

Peroxisome proliferator-activated receptors (PPAR) regulate the expression of genes involved in lipid metabolism, energy production, and inflammation. Their role in ischaemia-reperfusion (I/R) is less clear, although research indicates involvement of PPARs in some forms of preconditioning. This study aimed to explore the effects of PPAR-α activation on the I/R injury and potential cardioprotective downstream mechanisms involved. Langendorff-perfused hearts of rats pretreated with the selective PPAR-α agonist WY-14643 (WY, pirinixic acid; 3 mg·(kg body mass)·day -1; 5 days) were subjected to 30 min ischaemia - 2 h reperfusion with or without the phosphatidylinositol 3-kinase (PI3K)-Akt inhibitor wortmannin for the evaluation of functional (left ventricular developed pressure, LVDP) recovery, infarct size (IS), and reperfusion-induced arrhythmias. A 2-fold increase in baseline PPAR-α mRNA levels (qPCR) in the WY-treated group and higher post-I/R PPAR-α levels compared with those in untreated controls were accompanied by similar changes in the expression of PPARα target genes PDK4 and mCPT-1, regulating glucose and fatty acid metabolism, and by enhanced Akt phosphorylation. Post-ischaemic LVDP restoration in WY-treated hearts reached 60% ± 9% of the pre-ischaemic values compared with 24% ± 3% in the control hearts (P < 0.05), coupled with reduced IS and incidence of ventricular fibrillation that was blunted by wortmannin. Results indicate that PPAR-α up-regulation may confer preconditioning-like protection via metabolic effects. Downstream mechanisms of PPAR-α-mediated cardioprotection may involve PI3K-Akt activation