title: Oxidative stress-associated impairment of proteasome activity during ischemia-reperfusion injury.
abstract: Numerous studies indicate a role for oxidative stress in the neuronal degeneration and cell death that occur during ischemia-reperfusion injury. Recent data suggest that inhibition of the proteasome may be a means by which oxidative stress mediates neuronal cell death. In the current study, the authors demonstrate that there is a time-dependent decrease in proteasome activity, which is not associated with decreased expression of proteasome subunits, after cerebral ischemia-reperfusion injury. To determine the role of oxidative stress in mediating proteasome inhibition, ischemia-reperfusion studies were conducted in mice that either overexpressed the antioxidant enzyme glutathione peroxidase [GPX 1(+)], or were devoid of glutathione peroxidase activity (GPX -/-). After ischemia-reperfusion, GPX 1(+) mice displayed decreased infarct size, attenuated neurologic impairment, and reduced levels of proteasome inhibition compared with either GPX -/- or wild type mice. In addition, GPX 1(+) mice displayed lower levels of 4-hydroxynonenal-modified proteasome subunits after ischemia-reperfusion injury. Together, these data indicate that proteasome inhibition occurs during cerebral ischemia-reperfusion injury and is mediated, at least in part, by oxidative stress.
authors.affiliation: Sanders-Bronwn Research Center on Aging, Department of Biochemistry, University of Kentucky, Lexington 40536-0230, USA.
authors.forename: J N
authors.initials: JN
authors.lastname: Keller
authors.forename: F F
authors.initials: FF
authors.lastname: Huang
authors.forename: H
authors.initials: H
authors.lastname: Zhu
authors.forename: J
authors.initials: J
authors.lastname: Yu
authors.forename: Y S
authors.initials: YS
authors.lastname: Ho
authors.forename: T S
authors.initials: TS
authors.lastname: Kindy
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic / Q000235:genetics; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology
chemical_list: D009097:Multienzyme Complexes; D005979:Glutathione Peroxidase; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex