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Role of protein kinase C in ischemic preconditioning: player or spectator?

Although it may be debatable whether preconditioning will ever fulfill its clinical expectations, the hope that a new therapeutic modality may emerge from this fascinating phenomenon has given great impetus to the search for its underlying mechanism. Preconditioning is unquestionably a powerful phenomenon, it is readily and consistently demonstrable under many experimental conditions, and it has just celebrated its 10th birthday.1 In view of all this, it is perhaps surprising that the precise mechanism of preconditioning remains elusive and recently has become the subject of controversy.

An observer of the preconditioning literature could, at first sight, be forgiven for concluding that the precise mechanism is established and that protein kinase C (PKC) activation is a pivotal common factor that links a spectrum of receptor-mediated triggers of preconditioning. Downey and colleagues, now supported by other investigators (reviewed in References 2 and 3),2 3 have developed the compelling hypothesis that stimulation of a variety of G protein–coupled receptors (eg, adenosine A1, α1-adrenergic, muscarinic, bradykinin, and endothelin-1 receptors) results in the activation of PKC. This, in turn, leads to the physical translocation of PKC from the cytoplasm to the sarcolemma, where it phosphorylates a substrate protein (possibly the ATP-sensitive K+ [KATP] channel4 ) and thereby confers resistance to ischemia. Support for this attractive hypothesis comes from a wealth of studies (most of which rely upon indirect evidence in the absence of PKC activity measurements) with activators and inhibitors of PKC or its translocation process, with receptor agonists and antagonists, and with agents that interfere with the signaling pathways between various receptors and PKC (reviewed in References 5 and 6).

Considering the substantial body of evidence supporting the involvement of PKC activation in the preconditioning phenomenon, the observer could again be forgiven for wondering …