Platelet activating factor: the good and the bad in the ischemic/reperfused heart

Abstract

The present review is focused on the dual role played by platelet-activating factor (PAF) in ischemia and reperfusion (I/R) injury of the heart. Although the involvement of PAF in the pathogenesis of myocardial reperfusion injury is well established, in the last few years it has emerged that very low concentrations of PAF exert cardioprotective effects, comparable to that afforded by ischemic preconditioning (IP). PAF is a potent phosphoglyceride involved in different pathophysiological conditions affecting the cardiovascular system, including the development of myocardial I/R injury. PAF is released from the I/R myocardium in concentrations (1-10 nmol/L) high enough to negatively modulate coronary circulation as well as electrical and contractile activities. PAF may act either directly, via generation of secondary mediators, or through the activation of inflammatory cells like platelets and polymorphonuclear neutrophils, which exacerbate postischemic myocardial injury. The effects of PAF are mediated through specific receptors (PAFRs) that belong to the superfamily of G protein-coupled receptors. Since cardiomyocytes not only produce PAF but also possess PAFRs, it is likely that PAF acts as an autocrine/paracrine mediator. Although the negative effects exerted by high concentrations of PAF are well established, several recent findings from our and other laboratories have demonstrated that very low concentrations (pmol/L) of PAF infused before ischemia induce cardioprotective effects similar to those afforded by IP, and that endogenous PAF production participates in the induction of IP itself. The IP-like action exerted by low concentrations of PAF is due to the activation/phosphorylation of kinases included in the reperfusion injury salvage kinase (RISK) pathway, such as protein kinase C, Akt/PkB and nitric oxide synthase. Together with the activation of mitochondrial K(ATP) channels, these events may allow prevention of mitochondrial permeability transition pores opening at reperfusion. Moreover, the nitric oxide-dependent S-nitrosylation of L-type Ca(2+) channels induced by PAF reduces intracellular Ca(2+) overload.