A positive feedback loop between nitric oxide and amyloid β (1-42) accelerates mitochondrial damage in human lens epithelial cells. (15th April 2017)

• Record Type: Journal Article
• Authors: Nagai, Noriaki; Ito, Yoshimasa; Shibata, Teppei; Kubo, Eri; Sasaki, Hiroshi
• Is Part Of: Toxicology. Volume 381(2017)
• Page Start: 19
• Page End: 30
• Publication Date: 2017-04-15
• Subjects: Abs absorbance -- ADAM10 a disintegrin and metalloprotease domain protease 10 -- AG aminoguanidine -- APP amyloid precursor protein -- Aβ amyloid β -- BACE1 β site APP cleaving enzyme -- CCO cytochrome c oxidase -- DDC diethyldithiocarbamate -- DMEM Dulbecco's modified Eagle's medium -- DSF disulfiram -- ECE endothelin converting enzyme -- GAPDH glyceraldehyde-3-phosophate dehydrogenase -- H2O2 hydrogen peroxide -- HLE cell human lens epithelial cells -- IFN-γ interferon-gamma -- iNOS inducible nitric oxide synthase -- LPS lipopolysaccharide -- NEP neprilysin -- NFκB nuclear factor-kappa B -- NO nitric oxide -- PS presenilin -- ROS reactive oxygen species -- TNF-α tumor necrosis factor-α; Amyloid β -- Nitric oxide -- Lens epithelial cells -- Cytochrome c oxidase -- Cataract; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2017.02.014
• Languages: English
• ISSNs: 0300-483X

Abstract

Graphical abstract: Abstract: We have reported that excessive nitric oxide (NO), like other reactive oxygen species (ROS), causes a decrease in cytochrome c oxidase (CCO) activity and ATP levels (mitochondrial damage) resulting in lens opacity. In addition, previous reports have shown that oxidative stress caused by ROS enhances amyloid β (Aβ) production in mammalian lenses, and that Aβ1-42 stimulates inducible nitric oxide synthase (iNOS) promoter activity. Based on these reports, we investigated the relationship between NO and Aβ1-42 production in human lens epithelial (HLE) cells. iNOS was induced by the co-incubation of HLE cells with 1000 IU interferon-γ (IFN-γ) and 100 ng/ml lipopolysaccharide (LPS) for 48 h. This led to enhanced NO release, an increase in the gene expression levels of proteins related to Aβ production, and the cellular accumulation of Aβ1-42 . Moreover, both aminoguanidine (AG, a selective inhibitor of iNOS) and diethyldithiocarbamate (DDC, a nuclear factor-kappa B (NFκB) inhibitor) attenuated these changes in IFN-γ and LPS stimulated HLE cells. Based on our finding that Aβ1-42 accumulation is induced by co-incubation of HLE cells with both IFN-γ and LPS, we prepared a HLE cell model with Aβ1-42 accumulation (Aβ-accumulated-HLE cell model) by pre-stimulating cells with IFN-γ and LPS for 48 h. Aβ1-42 accumulation caused NO production via iNOS, resulting in an enhancement in the mRNA levels for enzymes necessary for the proteolysis of amyloid precursor protein (APP) to Aβ in HLE cells. In addition, excessive NO produced in response to Aβ1-42 accumulation led to a decrease in CCO activity and ATP levels. Taken together, we hypothesize that excessive NO production in the lens epithelium enhances Aβ1-42 production, and that this enhancement accelerates NO release. The enhancement in NO production in the lens epithelium based on positive feedback (NO-Aβ positive feedback loop, a vicious cycle) may promote the onset of cataracts (lens opacification) via the decrease in CCO activity and ATP levels. These findings provide significant information that can be used to design further studies aimed at developing anti-cataract drugs.