Proteasome inhibition ablates activation of NF-kappa B in myocardial reperfusion and reduces reperfusion injury.
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.
Pye
Joseph
J
Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27516, USA.
Ardeshirpour
Farhad
F
McCain
Arlene
A
Bellinger
Dwight A
DA
Merricks
Elizabeth
E
Adams
Julian
J
Elliott
Peter J
PJ
Pien
Christine
C
Fischer
Thomas H
TH
Baldwin
Albert S
AS
Nichols
Timothy C
TC
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D003402:Creatine Kinase / Q000097:blood; D052279:Creatine Kinase, MB Form; D003546:Cysteine Endopeptidases; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007527:Isoenzymes / Q000097:blood; D008297:Male; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000503:physiopathology; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D013552:Swine; D019210:Troponin I / Q000097:blood
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009097:Multienzyme Complexes; D016328:NF-kappa B; C411422:PS519; D019210:Troponin I; D003402:Creatine Kinase; D052279:Creatine Kinase, MB Form; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine