Cell Membrane Repair as a Mechanism for Ischemic Preconditioning?

Since its original description nearly 25 years ago, the phenomenon of ischemic preconditioning (IPC) continues to captivate a great amount of research interest. The ability to render the myocardium resistant to lethal ischemia/reperfusion injury by preconditioning it with a brief episode of ischemia and reperfusion1 has remained largely a laboratory phenomenon, with only a handful of proof-of-concept clinical studies realizing its true potential.2–4 Of course, the need to apply the IPC protocol before the index myocardial ischemic event has restricted its clinical application to planned cardiac surgery3 or percutaneous coronary intervention,4 settings in which the index myocardial ischemic event can be reliably predicted. The ability to noninvasively reproduce IPC cardioprotection by applying the IPC stimulus to the upper arm or leg with a blood pressure cuff to induce ischemia and reperfusion has also facilitated its clinical translation.3,4 In contrast, interrupting myocardial reperfusion with short-lived episodes of myocardial ischemia, as in ischemic postconditioning,5 an intervention that can be applied at the time of myocardial reperfusion, has been rapidly translated into the clinical setting.6Article see p 2565 Although an enormous research effort has been invested in elucidating the underlying mechanism of IPC, the actual pathway that mediates cardioprotection remains unclear. The current paradigm suggests that ≥1 brief episodes of ischemia and reperfusion that make up the IPC stimulus generate autoacoids such as adenosine, bradykinin, and opioids, which then recruit a number of signaling pathways through the activation of their respective receptors (see the Figure).7 Many of these signal transduction pathways converge on the mitochondria, resulting in the generation of oxidative stress, which activates downstream kinase mediators of cardioprotection. The sheer number and diversity of these signal transduction pathways linked to IPC, and the complexity with which they interact, can at times be …