A Sphingosine Kinase Form 2 Knockout Sensitizes Mouse Myocardium to Ischemia/Reoxygenation Injury and Diminishes Responsiveness to Ischemic Preconditioning

Figure 6

Suggested pathways for the increased susceptibility of SphK2 KO hearts to ischemia-reperfusion injury and decreased sensitivity to ischemic preconditioning. Ischemic preconditioning of wild-type (WT) hearts leads to the release of sphingosine 1-phosphate (S1P) via pannexin-1 (Px1) /P2X₇ channels, and this S1P then binds to G-protein-coupled receptors (GPCRs) triggering cell signaling pathways that are protective in ways that include preventing the opening of the mitochondrial permeability transition pore (mPTP), which is known to trigger cell injury. In the Sphk2 KO hearts, the level of S1P is reduced below the threshold necessary to trigger protective cell signaling pathways. The mPTP can also be opened by increased mitochondrial accumulation of Ca²⁺, and this can be enhanced by reactive oxygen species (ROS). In SphK2 KO hearts, the absence of adequate levels of S1P leads to defective cytochrome oxidase (COX) assembly which could lead to the generation of ROS that likely supports mPTP opening.