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Am J Physiol Heart Circ Physiol 284: H919-H926, 2003. First published November 7, 2002; doi:10.1152/ajpheart.00851.2002
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Vol. 284, Issue 3, H919-H926, March 2003

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

Joseph Pye1,2, Farhad Ardeshirpour1,2, Arlene McCain1,2, Dwight A. Bellinger2,3, Elizabeth Merricks2, Julian Adams6, Peter J. Elliott6, Christine Pien6, Thomas H. Fischer2, Albert S. Baldwin Jr.4,5, and Timothy C. Nichols1,2

Departments of 1 Medicine and 2 Pathology and Laboratory Medicine, 3 Division of Laboratory Animal Medicine, 4 Lineberger Comprehensive Cancer Center, 5 Department of Biology and Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina 27516; and 6 Millennium Pharmaceuticals, Cambridge, Massachusetts 02139

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-kappa B (NF-kappa B) plays a critical role in reperfusion injury. NF-kappa B is usually bound to its inhibitor, Ikappa B, and classic activation of NF-kappa B occurs when the 20S proteasome degrades Ikappa B that has been phosphorylated and ubiquitinated. In this study, activation of NF-kappa B 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-kappa B 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-kappa B activation.

inflammation; myocardial contraction; multienzyme complexes; transcription factors


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