Figure 2 Signalling pathways of ischaemic conditioning

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Figure 2 Signalling pathways of ischaemic conditioning Figure 2 | Signalling pathways of ischaemic conditioning. This schema depicts the major signalling pathways and cardioprotective effects of the various forms of ischaemic conditioning. Remote ischaemic conditioning is performed by applying one or more cycles of brief ischaemia and reperfusion (IR) to the upper or lower limb by inflating and deflating a blood-pressure cuff placed on the upper arm or thigh. Through the production of a blood-borne factor(s) and the stimulation of a neural pathway, the cardioprotective signal is conveyed to the heart where prosurvival signalling pathways within the cardiomyocyte mediate the cardioprotective effect. These signalling pathways are similar to those recruited by ischaemic preconditioning and postconditioning and targeted by pharmacological cardioprotection strategies. The signalling cascade underlying cardioprotection begins at the cardiomyocyte plasma membrane with the activation of G-protein-coupled or cytokine receptors by autacoids such as adenosine, bradykinin, or opioids (released in response to the ischaemic conditioning stimulus). This process results in the recruitment of signalling pathways such as the Reperfusion Injury Salvage Kinase (RISK) pathway (PI3K–Akt and Mek1/2–Erk1/2), Survivor Activator Factor Enhancement (SAFE) pathway (TNF and JAK–STAT), and the cGMP–protein kinase G (PKG) pathway. These salvage pathways have been shown to activate downstream mediators such as endothelial nitric oxide synthase (eNOS), glycogen synthase kinase (GSK)-3β, hexokinase II (HKII), protein kinase Cε (PKCε), and the mitochondrial ATP-dependent potassium channel (KATP), which then mediate an inhibitory effect on mitochondrial permeability transition pore (MPTP) opening. LV, left ventricular; MI, myocardial infarction; ROS, reactive oxygen species. Hausenloy, D. J. & Yellon, D. M. (2016) Ischaemic conditioning and reperfusion injury Nat. Rev. Cardiol. doi:10.1038/nrcardio.2016.5