Abstract
See related article, pages 307–314 Preconditioning (PreC) and postconditioning (PostC) have been shown to initiate a number of signaling cascades that reduce cell death. However, the mechanisms by which these signals reduce cell death have been elusive.1 PreC has been shown to phosphorylate and thereby inhibit glycogen synthase kinase (GSK)-3β, and perfusion with GSK inhibitors has been shown to reduce cell death induced by ischemia/reperfusion, when added before ischemia2 or when added at the start of reperfusion.3–5 These studies are consistent with data in other tissues showing that inhibition of GSK-3β reduces apoptosis. Information regarding the mechanism by which inhibition of GSK protects has been provided by Juhaszova et al,6 who report that inhibition of GSK-3β delays the opening of the mitochondrial permeability transition pore (MPT) (see the Figure). The MPT is a large-conductance pore in the inner mitochondrial membrane which is opened under conditions associated with ischemia/reperfusion, such as high matrix reactive oxygen species and high matrix calcium. Pharmacological inhibitors of the MPT have been shown to reduce ischemia/reperfusion injury, suggesting that activation of MPT might have a role in ischemia/reperfusion-mediated cell death. However the molecular components of the MPT have not been identified.7 Figure. Nishino et al8 raise 2 questions: (1) whether inhibition of GSK is required for protection in mice; and (2) whether inhibition of GSK is protective in mouse hearts. PreC and PostC activate a number of redundant signaling pathways that lead to inhibition of MPT. The relative importance of different pathways may vary depending on the model and species. Previous studies6 have suggested that inhibition of GSK is a major signaling pathway that results in inhibition of MPT; this is illustrated with the large arrow. However, other pathways exist and it is not surprising that under different …
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