PR-39 and PR-11 peptides inhibit ischemia-reperfusion injury by blocking proteasome-mediated I kappa B alpha degradation.
PR-39 inhibits proteasome-mediated I kappa B alpha degradation and might protect against ischemia-reperfusion injury. We studied PR-39, its truncated form PR-11, and a mutant PR-11AAA, which lacks the ability to prevent I kappa B alpha degradation, in a rat heart ischemia-reperfusion model. After 30 min of ischemia and 24 h of reperfusion, cardiac function, infarct size, neutrophil infiltration, and myeloperoxidase activity were measured. Intramyocardial injection of 10 nmol/kg PR-39 or PR-11 at the time of reperfusion reduced infarct size by 65% and 57%, respectively, which improved blood pressure, left ventricular systolic pressure, and relaxation and contractility (+/-dP/dt) compared with vehicle controls 24 h later. Neutrophil infiltration, myeloperoxidase activity, and the expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule 1 were reduced. Thus PR-39 and PR-11 effectively inhibit myocardial ischemia-reperfusion injury in the rat in vivo. This effect is mediated by inhibition of I kappa B alpha degradation and subsequent inhibition of nuclear factor-kappa B-dependent adhesion molecules. The active sequence is located in the first 11 amino acids, suggesting a potential for oligopeptide therapy as an adjunct to revascularization.
Bao
J
J
Angiogenesis Research Center, Dartmouth Medical School, Hanover, New Hampshire 03756, USA.
Sato
K
K
Li
M
M
Gao
Y
Y
Abid
R
R
Aird
W
W
Simons
M
M
Post
M J
MJ
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D009504:Neutrophils / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology; D019010:Vascular Cell Adhesion Molecule-1 / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D009097:Multienzyme Complexes; C000606204:NFKBIA protein, human; C000606206:Nfkbia protein, rat; D010446:Peptide Fragments; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C072212:PR 39; D000072000:NF-KappaB Inhibitor alpha; D009195:Peroxidase; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex