Platelet-activating factor induces cardioprotection in isolated rat heart akin to ischemic preconditioning: role of phosphoinositide 3-kinase and protein kinase C activation

Abstract

. Platelet-activating factor induces cardioprotection in isolated rat heart akin to ischemic preconditioning: role of phosphoinositide 3-kinase and protein kinase C activation. Am J Physiol Heart Circ Physiol 288: H2512-H2520, 2005. First published January 6, 2005; doi:10.1152/ajpheart.00599.2004.-Ischemic preconditioning (IP) is a cardioprotective mechanism against myocellular death and cardiac dysfunction resulting from reperfusion of the ischemic heart. At present, the precise list of mediators involved in IP and the pathways of their mechanisms of action are not completely known. The aim of the present study was to investigate the role of platelet-activating factor (PAF), a phospholipid mediator that is known to be released by the ischemic-reperfused heart, as a possible endogenous agent involved in IP. Experiments were performed on Langendorff-perfused rat hearts undergoing 30 min of ischemia followed by 2 h of reperfusion. Treatment with a low concentration of PAF (2 ϫ 10 Ϫ11 M) before ischemia reduced the extension of infarct size and improved the recovery of left ventricular developed pressure during reperfusion. The cardioprotective effect of PAF was comparable to that observed in hearts in which IP was induced by three brief (3 min) periods of ischemia separated by 5-min reperfusion intervals. The PAF receptor antagonist WEB-2170 (1 ϫ 10 Ϫ9 M) abrogated the cardioprotective effect induced by both PAF and IP. The protein kinase C (PKC) inhibitor chelerythrine (5 ϫ 10 Ϫ6 M) or the phosphoinositide 3-kinase (PI3K) inhibitor LY-294002 (5 ϫ 10 Ϫ5 M) also reduced the cardioprotective effect of PAF. Western blot analysis revealed that following IP treatment or PAF infusion, the phosphorylation of PKC-⑀ and Akt (the downstream target of PI3K) was higher than that in control hearts. The present data indicate that exogenous applications of low quantities of PAF induce a cardioprotective effect through PI3K and PKC activation, similar to that afforded by IP. Moreover, the study suggests that endogenous release of PAF, induced by brief periods of ischemia and reperfusion, may participate to the triggering of the IP of the heart. ischemia-reperfusion; WEB-2170; LY-294002 ISCHEMIC PRECONDITIONING (IP) is the phenomenon whereby brief periods of ischemia and reperfusion increase the resistance to myocardial infarction and contractile dysfunction induced by a subsequent sustained episode of ischemia (9, 34 -36). In all species tested, the beneficial effects of IP include protection against necrotic and apoptotic cell death. In some species, it has been shown that IP also induces the prevention of ischemia-reperfusion-induced arrhythmias, a faster recovery from reperfusion-induced myocardial stunning, and a protection of microvasculature function (for reviews, see Refs. 33 and 35

Catestatin reduces myocardial ischaemia/reperfusion injury: involvement of PI3K/Akt, PKCs, mitochondrial KATP channels and ROS signalling

“…The methods were similar to those previously described [1,33,35,36,[39][40][41]. In brief, after anaesthesia chest was opened and heart excised.…”

“…The hearts were instrumented to record coronary pressure and left ventricular pressure (LVP), electrically paced at 280 b.p.m. and kept in a temperature-controlled chamber (37°C) [1,33,35,36,[39][40][41].…”

“…In Group 3 and 4, the large spectrum PKC inhibitor, chelerythrine (CHE, 5μM; CST-Post+CHE Group) or the selective inhibitor of PI3K/Akt, LY-294002 (LY, 50μM; CST-Post+LY Group) were used to test the involvement of these pivotal kinases in cardioprotection scenario [35,42].…”

“…Infarct areas were assessed at the end of the experiment as previously described [32,34,35,[38][39][40]. In brief, immediately after reperfusion hearts were rapidly removed from the perfusion apparatus and the LV dissected into 2-3 mm circumferential slices.…”

“…The mitoK ATP channels via multiple mechanisms, including the partial depolarization of the mitochondrial membrane, may favour reactive oxygen species (ROS)-signalling, which may lead to a re-activation of a pool of PKCs [15,35,53]. In particular, in concert with mitoK ATP channels, the intramitochondrial protein kinase Cε (PKCε) activation may take part to the so-called "memory-associated protection".…”