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

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 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.

Aloperine Protects Mice against Ischemia-Reperfusion (IR)-Induced Renal Injury by Regulating PI3K/AKT/mTOR Signaling and AP-1 Activity

“…Indeed, the addition of aloperine significantly enhanced hypoxiainduced nuclear cFos and antiapoptotic Bcl2 expression, which was completely abrogated by the addition of TanIIA, an AP1 inhibitor. Collectively, our data support that aloperine regulates AP1 activity, by which it enhances SOD expression injury (62,63). However, we cannot exclude the feasibility that aloperine regu lates additional pathways other than the PI3K/Akt/mTOR signaling in the setting of IRinduced acute renal injury.…”

TGF-β improves myocardial function and prevents apoptosis induced by anoxia–reoxygenation, through the reduction of endoplasmic reticulum stress

“…Activated PI3K and Akt are each sufficient to protect cardiomyocytes against apoptosis, and activation of Akt blocked apoptosis (Jie et al 2012). Activation of PI3K/Akt pathway may be useful to promote cardiomyocytes survival in the damaged heart (Ravingerova et al 2012). The data demonstrated that LY-294002 blocked TGF-β elicited decreased the Caspase3.…”

Effect of hypercholesterolaemia on myocardial function, ischaemia–reperfusion injury and cardioprotection by preconditioning, postconditioning and remote conditioning

“…Although this effect has not yet been corroborated in subsequent studies and the underlying mechanism is unclear, it is pausible that activation of PPARα, which is markedly down‐regulated in hypercholesterolaemic rat heart after ischaemia/reperfusion, and subsequent activation of the PI3K/Akt/eNOS pathway may restore the lost cardioprotection in hypercholesterolaemic hearts. In this context, PPARα up‐regulation confers preconditioning‐like protection against ischaemia/reperfusion via metabolic effects whereas PI3K/Akt activation may also be involved in the downstream mechanisms (Ravingerová et al ., ; ).…”