Shifting paradigms for ischaemic preconditioning: AUTHOR'S RETROSPECTIVE

This editorial refers to an article by Z. Cai et al . [11][1] published in Cardiovascular Research in 2008 (see [Box 1][2]). It is accompanied by an editorial by G. Heusch, pp. 214–215, this issue, as part of this Spotlight on Landmark Papers in Cardiovascular Research . One of the most intensively studied phenomena in cardiovascular research is ischaemic preconditioning (IPC), the observation that exposure of the heart to several short (e.g. 5 min) cycles of ischaemia (I5) and reperfusion (R5) will protect against injury caused by a subsequent prolonged (e.g. 30 min) episode of ischaemia (I30) followed by reperfusion.1 The onset of cardioprotection is immediately following the IPC stimulus and lasts for only several hours,1 but is followed by a second window of cardioprotection with the onset ∼24 h after IPC and lasting for several days thereafter.2,3 Based on thousands of research studies spanning two decades, a dominant paradigm was established that acute- or early-phase cardioprotection was rapid but short-lived because it involved transient post-translational modifications of existing proteins, whereas delayed or late-phase cardioprotection was slower to develop but longer lasting because it involved de novo synthesis of mRNAs and their translation into proteins. A remarkably long list of signal transduction pathways, biochemical reactions, and gene products have been implicated in the response of the heart to IPC.4–6 For several molecular targets, the paradigm holds: the activity of the protein is regulated during the acute phase of protection, whereas expression of the protein is regulated during the late phase. It is conventional wisdom that the IPC stimulus-response pathway is centred in cardiomyocytes. Indeed, some investigators have attempted to develop reductionist cell culture models in which cardiomyocytes are exposed to oxygen and glucose deprivation for various lengths of time,7 although others in the … [1]: #ref-11 [2]: #F2