title: Oxidative Stress Alters the Morphology and Toxicity of Aortic Medial Amyloid.
abstract: The aggregation and fibril deposition of amyloid proteins have been implicated in a range of neurodegenerative and vascular diseases, and yet the underlying molecular mechanisms are poorly understood. Here, we use a combination of cell-based assays, biophysical analysis, and atomic force microscopy to investigate the potential involvement of oxidative stress in aortic medial amyloid (AMA) pathogenesis and deposition. We show that medin, the main constituent of AMA, can induce an environment rich in oxidative species, increasing superoxide and reducing bioavailable nitric oxide in human cells. We investigate the role that this oxidative environment may play in altering the aggregation process of medin and identify potential posttranslational modification sites where site-specific modification and interaction can be unambiguously demonstrated. In an oxidizing environment, medin is nitrated at tyrosine and tryptophan residues, with resultant effects on morphology that lead to longer fibrils with increased toxicity. This provides further motivation to investigate the role of oxidative stress in AMA pathogenicity.
authors.affiliation: Institute of Integrative Biology, University of Liverpool, Liverpool, UK.
authors.forename: Hannah A
authors.initials: HA
authors.lastname: Davies
authors.affiliation: Institute of Integrative Biology, University of Liverpool, Liverpool, UK; Technology Directorate, University of Liverpool, Liverpool, UK.
authors.forename: Marie M
authors.initials: MM
authors.lastname: Phelan
authors.affiliation: Institute of Integrative Biology, University of Liverpool, Liverpool, UK.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Wilkinson
authors.affiliation: Office of Research, Phoenix Veterans Affairs Health Care System, Phoenix, Arizona.
authors.forename: Raymond Q
authors.initials: RQ
authors.lastname: Migrino
authors.affiliation: Office of Research, Phoenix Veterans Affairs Health Care System, Phoenix, Arizona.
authors.forename: Seth
authors.initials: S
authors.lastname: Truran
authors.affiliation: Office of Research, Phoenix Veterans Affairs Health Care System, Phoenix, Arizona.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Franco
authors.affiliation: Institute of Integrative Biology, University of Liverpool, Liverpool, UK.
authors.forename: Lu-Ning
authors.initials: LN
authors.lastname: Liu
authors.affiliation: Institute of Integrative Biology, University of Liverpool, Liverpool, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Longmore
authors.affiliation: Institute of Integrative Biology, University of Liverpool, Liverpool, UK. Electronic address: j.madine@liv.ac.uk.
authors.forename: Jillian
authors.initials: J
authors.lastname: Madine
mesh_terms: D000954:Antigens, Surface / Q000378:metabolism / Q000633:toxicity*; D001011:Aorta / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008894:Milk Proteins / Q000378:metabolism / Q000633:toxicity*; D009566:Nitrates / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*
chemical_list: D000954:Antigens, Surface; C098942:MFGE8 protein, human; D008894:Milk Proteins; D009566:Nitrates