Proteasome inhibition ablates activation of NF-κB in myocardial reperfusion and reduces reperfusion injury

Abstract
Both acute coronary occlusion and reperfusion of an infarct-related artery lead to significant myocardial cell death. Recent evidence has been presented that activation of the transcription factor nuclear factor-κB (NF-κB) plays a critical role in reperfusion injury. NF-κB is usually bound to its inhibitor, IκB, and classic activation of NF-κB occurs when the 20S proteasome degrades IκB that has been phosphorylated and ubiquitinated. In this study, activation of NF-κB was inhibited by systemic administration of a 20S proteasome inhibitor (PS-519) in a porcine model of myocardial reperfusion injury. The experimental protocol induced myocardial ischemia in the distribution of the left anterior descending coronary artery for 1 h with subsequent reperfusion for 3 h. A single systemic treatment with PS-519 reduced 20S proteasome activity; blocked activation of NF-κB induced by reperfusion; reduced creatine kinase, creatine kinase-muscle-brain fraction, and troponin I release from the myocardium; preserved regional myocardial function measured by segmental shortening; significantly reduced the size of myocardial infarction; and exhibited no acute toxicity. These data show that myocardial reperfusion injury can be inhibited by using proteasome inhibitors, which likely function through the inhibition of NF-κB activation.