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 kappaB alpha degradation and might pro tect against ischemia-reperfusion injury. We studied PR-39, its truncated f orm PR-11, and a mutant PR-11AAA, which lacks the ability to prevent I kapp aB alpha degradation, in a rat heart ischemia-reperfusion model. After 30 m in of ischemia and 24 h of reperfusion, cardiac function, infarct size, neu trophil infiltration, and myeloperoxidase activity were measured. Intramyoc ardial injection of 10 nmol/kg PR-39 or PR-11 at the time of reperfusion re duced infarct size by 65% and 57%, respectively, which improved blood press ure, left ventricular systolic pressure, and relaxation and contractility ( +/-dP/dt) compared with vehicle controls 24 h later. Neutrophil infiltratio n, myeloperoxidase activity, and the expression of intercellular adhesion m olecule-1 and vascular cell adhesion molecule 1 were reduced. Thus PR-39 an d PR-11 effectively inhibit myocardial ischemia-reperfusion injury in the r at in vivo. This effect is mediated by inhibition of I kappaB alpha degrada tion and subsequent inhibition of nuclear factor-kappaB-dependent adhesion molecules. The active sequence is located in the first 11 amino acids, sugg esting a potential for oligopeptide therapy as an adjunct to revascularizat ion.