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B
degradation
1 Angiogenesis Research Center, 2 Division of Molecular Medicine, Beth Israel Deaconess Medical Center, 3 Angiogenesis Research Center, Dartmouth Medical School, Hanover, New Hampshire 03756
PR-39 inhibits proteasome-mediated I
B
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
B
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
B
degradation and subsequent
inhibition of nuclear factor-
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.
rat; reactive oxygen species
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