PPAR-alpha activation as a preconditioning-like intervention in rats in vivo confers myocardial protection against acute ischaemia-reperfusion injury: involvement of PI3K-Akt
| Autor: | Táňa Ravingerová, S Carnicka, Tara Kelly, Eleftheria Galatou, Adriana Adameova, Nemčeková M, Antigone Lazou, Eleftheria Barlaka, V. Ledvényiová, Vinoth Kumar Megraj Khandelwal |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Physiology Myocardial Infarction Peroxisome proliferator-activated receptor Myocardial Reperfusion Injury Pharmacology Wortmannin chemistry.chemical_compound Chymases Physiology (medical) Medicine Animals PPAR alpha Phosphorylation Rats Wistar Protein kinase B Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors chemistry.chemical_classification Cardioprotection business.industry Arrhythmias Cardiac General Medicine medicine.disease Rats Up-Regulation Androstadienes Disease Models Animal Pyrimidines chemistry Pirinixic Acid Peroxisome Proliferators Peroxisome proliferator-activated receptor alpha Phosphatidylinositol 3-Kinase business Reperfusion injury Protein Kinases Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Canadian journal of physiology and pharmacology. 90(8) |
| ISSN: | 1205-7541 |
| Popis: | 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 PPAR-α 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. |
| Databáze: | OpenAIRE |
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