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

• Authors: Joseph Pye, Farhad Ardeshirpour, Arlene McCain, Dwight A Bellinger, Elizabeth Merricks, Julian Adams, Peter J Elliott, Christine Pien, Thomas H Fischer, Albert S Baldwin Jr, Timothy C Nichols
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 284 Issue 3 Pg. H919-26 (Mar 2003) ISSN: 0363-6135 [Print] United States
• PMID: 12424098 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Enzyme Inhibitors
• Isoenzymes
• Multienzyme Complexes
• NF-kappa B
• PS519
• Troponin I
• Creatine Kinase
• Creatine Kinase, MB Form
• Cysteine Endopeptidases
• Proteasome Endopeptidase Complex
• Acetylcysteine

Topics

• Acetylcysteine (analogs & derivatives, pharmacology)
• Animals
• Creatine Kinase (blood)
• Creatine Kinase, MB Form
• Cysteine Endopeptidases
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Female
• Isoenzymes (blood)
• Male
• Multienzyme Complexes (antagonists & inhibitors)
• Myocardial Ischemia (drug therapy, physiopathology)
• Myocardial Reperfusion
• Myocardial Reperfusion Injury (prevention & control)
• Myocardium (metabolism)
• NF-kappa B (antagonists & inhibitors, metabolism)
• Proteasome Endopeptidase Complex
• Swine
• Troponin I (blood)