Did a Classic Preconditioning Study Provide a Clue to the Identity of the Mitochondrial Permeability Transition Pore?

A classic article by Murry et al published in 1990 in Circulation Research showed that preconditioning slowed the rate of ATP breakdown during a subsequent sustained period of ischemia. The mechanism responsible for reduced ATP breakdown is still unknown, but perhaps it is related to the inhibition of F1-F0 ATPase. This is an attractive hypothesis, given several recent studies suggesting that the F1-F0 ATPase can form the mitochondrial permeability transition pore. Ischemic preconditioning (PC) is one of the more reproducible and robust forms of cardioprotection. A classic article by Murry et al1 was one of the original descriptions of PC. This article, along with others, demonstrated that the heart could initiate an adaptive signaling program that could lead to a significant reduction in infarct size. This article and an earlier article by this group2 reinvigorated the field of cardioprotection. This article showed that subjecting the heart to several brief periods of intermittent ischemia and reperfusion could protect the heart from a subsequent longer period of sustained ischemia. It was somewhat surprising that although the ischemically preconditioned hearts had an additional 20 minutes of ischemia, they had significantly less necrosis. This protection was initiated by as little as 5 minutes of reperfusion between short PC protocol and the extended period of ischemia and was lost if the last period of reperfusion was extended beyond 30 to 60 minutes. These data suggested that a rapid signaling pathway was involved in initiating cardioprotection. This classic article led to a revolution in the field of cardioprotection. The discovery of ischemic PC was followed by a large number of studies showing that this protection could also be initiated by pharmacological agents (pharmacological PC). A large number of signaling pathways were shown …