title: Platelet-activating factor induces cardioprotection in isolated rat heart akin to ischemic preconditioning: role of phosphoinositide 3-kinase and protein kinase C activation.
abstract: 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 x 10(-11) 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 x 10(-9) M) abrogated the cardioprotective effect induced by both PAF and IP. The protein kinase C (PKC) inhibitor chelerythrine (5 x 10(-6) M) or the phosphoinositide 3-kinase (PI3K) inhibitor LY-294002 (5 x 10(-5) M) also reduced the cardioprotective effect of PAF. Western blot analysis revealed that following IP treatment or PAF infusion, the phosphorylation of PKC-epsilon 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.
authors.affiliation: Dipartimento di Scienze Cliniche e Biologiche, ASO S. Luigi, Orbassano, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Penna
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Alloatti
authors.forename: Sandra
authors.initials: S
authors.lastname: Cappello
authors.forename: Donatella
authors.initials: D
authors.lastname: Gattullo
authors.forename: Giovanni
authors.initials: G
authors.lastname: Berta
authors.forename: Barbara
authors.initials: B
authors.lastname: Mognetti
authors.forename: Gianni
authors.initials: G
authors.lastname: Losano
authors.forename: Pasquale
authors.initials: P
authors.lastname: Pagliaro
mesh_terms: D000470:Alkaloids; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D053119:Benzophenanthridines; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002867:Chromones / Q000494:pharmacology; D003326:Coronary Circulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D009336:Necrosis; D010477:Perfusion; D010617:Phenanthridines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014230:Triazoles / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000470:Alkaloids; D001381:Azepines; D053119:Benzophenanthridines; D002316:Cardiotonic Agents; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D010617:Phenanthridines; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D014230:Triazoles; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C063964:bepafant; C016299:chelerythrine; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C