Figure 1.

This figure depicts a patient undergoing remote ischemic preconditioning using a blood pressure cuff on his right arm. The cycles of ischemia and reperfusion stimulate release of the cardioprotective factor from the afferent neuron. The cardioprotective factor travels systemically via the blood interacting with various cells, including cardiomyocytes. The cardioprotective factor facilitates the RISK and SAFE signaling cascades in cardiomyocytes. At the same time, the afferent neuron potentiates an action potential to nuclei in the brainstem. An unknown efferent neuron potentiates a signal to the heart which triggers cardioprotective signaling pathways such as RISK and SAFE. Volatile anesthetic agents have been shown to adjust hemodynamic properties of the body and stimulate RISK and SAFE signaling cascades in cardiomyocytes to achieve a protective effect. (A) Depicts the RISK signaling cascade. Adenosine, bradykinin or opioids bind to its G-protein coupled receptor which results in phosphorylation and activation of PI3K. PI3K will phosphorylate and activate Akt which has several downstream effects, the most notable is the interaction with GSK3β. Akt can phosphorylate and hence inhibit GSK3β. GSK3β normally activates and opens the MPTP, but inhibition of GSK3β through phosphorylation prevents the MPTP from opening and promotes cell survival and resistance to ischemic damage. Akt can also activate other signaling kinases such as eNOS, and PKC and inhibit pro-apoptotic factors such as bad and bax; (B) Depicts a PKC signaling cascade. Adenosine, bradykinin or opioids bind to its G-protein coupled receptor which results in phosphorylation and activation of PI3K. PI3K will phosphorylate and activate Akt, which will activate eNOS to produce nitric oxide (NO). NO will activate soluble guanylyl cyclase, which will activate protein kinase G (PKG), leading to activation of PKC. PKC can open the mitochondrial K_ATP channel, which can prevent MPTP activation and promote cell survival and resistance to ischemic damage, and (C) Depicts the SAFE signaling cascade. TNF-α can bind to TNF Receptor 2 (TNFR2) which will activate the JAK kinase. JAK will phosphorylate and activate STAT-3. STAT-3 can inhibit the pro-apoptotic factor Bad, as well as form a homodimer which can translocate into the nucleus of the cell. The dimerized STAT-3 can induce transcription, increasing the expression of genes for Bcl-2, an anti-apoptotic protein, and decrease the expression of genes for Bax, a pro-apoptotic protein. STAT-3 may also inactivate FOXO-1, another transcription factor which has been shown to induce the expression of apoptotic genes.