title: Proteasome inhibition by chronic oxidative stress in human trabecular meshwork cells.
abstract: The pathophysiologic mechanisms leading to the malfunction of the trabecular meshwork (TM)-Schlemm's canal (SC) outflow pathway in glaucoma are still unclear. We hypothesize that chronic oxidative stress may contribute to the malfunction of the outflow pathway by impairing the intracellular proteasome system of the cells, decreasing the ability of the tissue to modulate outflow resistance. To study the effects of chronic oxidative stress on proteasome function, primary cultures of human TM cells were incubated under 40% oxygen and proteasome activity was analyzed by measuring the accumulation of enhanced green fluorescent protein fused to a PEST motif. Changes in proteasome content, cellular senescence, and cell viability were also monitored. After 10 days of exposure to chronic oxidative stress, TM cells showed a marked decline in proteasome activity that was associated with premature senescence and decreased cell viability. These results suggest that proteasome failure may be involved in glaucoma pathophysiology.
authors.affiliation: Department of Ophthalmology, Duke University, Durham, NC 27710, USA.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Caballero
authors.forename: Paloma B
authors.initials: PB
authors.lastname: Liton
authors.forename: David L
authors.initials: DL
authors.lastname: Epstein
authors.forename: Pedro
authors.initials: P
authors.lastname: Gonzalez
mesh_terms: D002470:Cell Survival; D002478:Cells, Cultured; D016922:Cellular Senescence; D003546:Cysteine Endopeptidases; D005901:Glaucoma / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D049452:Green Fluorescent Proteins; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014129:Trabecular Meshwork / Q000201:enzymology* / Q000503:physiopathology
chemical_list: D008164:Luminescent Proteins; D009097:Multienzyme Complexes; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex