PPAR-alpha activation as a preconditioning-like intervention in rats in vivo confers myocardial protection against acute ischaemia-reperfusion injury: involvement of PI3K-Akt.
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.
Institute for Heart Research, Slovak Academy of Sciences and Centre of Excellence of SAS NOREG, Bratislava, Slovak Republic. usrdravi@savba.sk
Táňa
T
Ravingerová
Slávka
S
Carnická
Martina
M
Nemčeková
Veronika
V
Ledvényiová
Adriana
A
Adameová
Tara
T
Kelly
Eleftheria
E
Barlaka
Eleftheria
E
Galatou
Vinoth Kumar Megraj
VK
Khandelwal
Antigone
A
Lazou
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000150:complications / Q000503:physiopathology / Q000517:prevention & control; D053818:Chymases / Q000096:biosynthesis; D004195:Disease Models, Animal; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000503:physiopathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control*; D047493:PPAR alpha / Q000096:biosynthesis / Q000502:physiology*; D020025:Peroxisome Proliferators / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D058539:Phosphatidylinositol 3-Kinase / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000096:biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D011743:Pyrimidines / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D000077191:Wortmannin
D000730:Androstadienes; D047493:PPAR alpha; D020025:Peroxisome Proliferators; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C006253:pirinixic acid; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D053818:Chymases; C509231:Mcpt1 protein, rat; D000077191:Wortmannin