Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Anti-Bacterial Agents / pharmacology*
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Antimicrobial Cationic Peptides / pharmacology*
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Cells, Cultured
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Cysteine Endopeptidases / metabolism*
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DNA-Binding Proteins / metabolism*
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Endothelium, Vascular / cytology
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Endothelium, Vascular / metabolism
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Humans
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I-kappa B Proteins*
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Intercellular Adhesion Molecule-1 / metabolism
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Male
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Multienzyme Complexes / metabolism*
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Myocardial Reperfusion Injury / drug therapy*
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Myocardial Reperfusion Injury / metabolism
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Myocardium / metabolism
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NADPH Oxidases / metabolism
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NF-KappaB Inhibitor alpha
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Neutrophils / metabolism
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Peptide Fragments / pharmacology
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Peroxidase / metabolism
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Phosphoproteins / metabolism
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Proteasome Endopeptidase Complex
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Rats
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Rats, Sprague-Dawley
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Reactive Oxygen Species / metabolism
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Umbilical Veins / cytology
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Vascular Cell Adhesion Molecule-1 / pharmacology
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Ventricular Function, Left / drug effects
Substances
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Anti-Bacterial Agents
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Antimicrobial Cationic Peptides
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DNA-Binding Proteins
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I-kappa B Proteins
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Multienzyme Complexes
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NFKBIA protein, human
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Nfkbia protein, rat
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Peptide Fragments
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Phosphoproteins
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Reactive Oxygen Species
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Vascular Cell Adhesion Molecule-1
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Intercellular Adhesion Molecule-1
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PR 39
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NF-KappaB Inhibitor alpha
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Peroxidase
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NADPH Oxidases
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neutrophil cytosolic factor 1
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex