Activation of NF-κB is a critical element in the antiapoptotic effect of anesthetic preconditioning

Lu X, Liu H, Wang L, Schaefer S. Activation of NF-kappa B is a critical element in the antiapoptotic effect of anesthetic preconditioning. Am J Physiol Heart Circ Physiol 296: H1296-H1304, 2009. First published March 20, 2009; doi:10.1152/ajpheart.01282.2008.-Anesthetic preconditioning (APC), defined as brief exposure to inhalational anesthetics before cardiac ischemia-reperfusion (I/R), limits injury in both animal models and in humans. APC can result in the production of reactive oxygen species (ROS), and prior work has shown that APC can modify activation of NF-kappa B during I/R, with consequent reduction in the expression of inflammatory mediators. However, the role of NF-kappa B activation before I/R is unknown. Therefore, these experiments tested the hypothesis that APC-induced ROS results in activation of NF-kappa B before I/R, with consequent increased expression of antiapoptotic proteins such as Bcl-2 and decreased apoptosis. Experiments utilized an established perfused heart rat model of sevoflurane APC and I/R. The role of NF-kappa B was defined by a novel method of transient inhibition of the regulatory kinase IKK using the reversible inhibitor SC-514. In addition to functional measures of left ventricular developed and end-diastolic pressure, phosphorylation of I kappa B alpha and activation of NF-kappa B were measured along with cytosolic protein content of Bcl-2, release of cytochrome c, and degradation of caspase-3. APC resulted in ROS-dependent phosphorylation of I kappa B alpha and activation of NF-kappa B before I/R. APC also increased the expression of Bcl-2 before I/R. In addition to functional protection following I/R, APC resulted in lower release of cytochrome c and caspase-3 degradation. These protective effects of APC were abolished by transient inhibition of I kappa B alpha phosphorylation and NF-kappa B activation by SC-514 followed by washout. ROS-dependent activation of NF-kappa B by APC before I/R is a critical element in the protective effect of APC. APC reduces apoptosis and functional impairment by increasing Bcl-2 expression before I/R. Interventions that increase NF-kappa B activation before I/R should protect hearts from I/R injury.