Delayed preconditioning of myocardium: current perspectives

The protection conferred by ischemic preconditioning (PC) of myocardium occ urs in a bimodal time course. The early cardioprotection wanes rapidly and is succeeded by a delayed phase of protection. This "second window" lasts f or up to 72 hours, depending on species and end-point. A widely adopted par adigm for delayed PC is the following: 1) freely diffusible molecules or ra dicals, generated during the PC period, act in autocrine and/or paracrine m anner as triggers of cellular adaptation; 2) they cause the activation of a protein kinase signal cascade; 3) the activated kinases phosphorylate impo rtant substrate proteins. In the case of delayed PC, it is thought that the phosphorylation of transcription factors, initiating the synthesis of late appearing effector proteins that promote cell survival during subsequent i schemia, may be a crucial event. Investigation of the proximal components o f this sequence has altered our perceptions of several biological mediators , previously thought to be short acting, including adenosine, NO, free radi cals and bradykinin. Signal transduction components include protein kinase C, tyrosine kinases and various mitogen- and stress-activated protein kinas es but their patterns of regulation are complex and as yet poorly defined. Gene expression is modified in a regulated fashion to induce new proteins t hat promote cell repair and to protect against subsequent ischemia-reperfus ion insult. It is likely that the complex nature of the preconditioning sti mulus causes the activation of a variety of transcription factors, regulati ng a large number of target genes. So far, attention has focussed on a smal l number of protein products as potential distal mediators of delayed preco nditioning. These include the heat shock proteins, manganese superoxide dis mutase, inducible nitric oxide synthase, the ATP-sensitive potassium channe l and cyclo-oxygenase-2.