Ischemic preconditioning

The schematic provides a simplified overview of the potential mechanistic pathways underlying ischemic preconditioning (IPC) and postconditioning (IPost) which link the sarcolemma to the inhibition of the mitochondrial permeability transition pore (MPTP): (1) Indirect MPTP inhibition (shaded or blue): include those mechanisms that result in MPTP inhibition as an indirect effect of IPC and IPost on factors known to induce MPTP opening at the time of myocardial reperfusion, such as attenuating detrimental reactive oxygen species (ROS) production, preserving ATP levels, delaying pH correction at reperfusion and delaying restoration of physiological pH at reperfusion, and reducing mitochondrial and cytosolic calcium loading: and (2) Direct mPTP inhibition (unshaded or beige): those mechanisms that depend on a signal transduction pathway that begins at the cardiomyocyte plasma membrane with the activation of the G-protein coupled receptor by an autocoid such as adenosine, bradykinin, or opioids, which result in the recruitment of complex signal transduction pathways (for the sake of clarity only PI3K-Akt and MEK1/2-Erk1/2 pathways are shown on this diagram although a number of different signaling pathways have been implicated in both IPC and IPost) which terminate on the mitochondria and involve in some cases the translocation of protein kinases to the mitochondria. Clearly, there is a degree of overlap between these two groups- for example; both PKG and PI3K-Akt have been reported to influence intracellular calcium regulation by promoting the uptake of calcium via SERCA into the sarcoplasmic reticulum.