Abstract
Amyloidoses constitute a group of diseases in which soluble proteins aggregate and deposit extracellularly in tissues. Nonhereditary apolipoprotein A-I (apoA-I) amyloid is characterized by deposits of nonvariant protein in atherosclerotic arteries. Despite being common, little is known about the pathogenesis and significance of apoA-I deposition. In this work we investigated by fluorescence and biochemical approaches the impact of a cellular microenvironment associated with chronic inflammation on the folding and pro-amyloidogenic processing of apoA-I. Results showed that mildly acidic pH promotes misfolding, aggregation, and increased binding of apoA-I to extracellular matrix elements, thus favoring protein deposition as amyloid like-complexes. In addition, activated neutrophils and oxidative/proteolytic cleavage of the protein give rise to pro amyloidogenic products. We conclude that, even though apoA-I is not inherently amyloidogenic, it may produce non hereditary amyloidosis as a consequence of the pro-inflammatory microenvironment associated to atherogenesis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid / metabolism*
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Anilino Naphthalenesulfonates / metabolism
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Animals
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Apolipoprotein A-I / chemistry
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Apolipoprotein A-I / metabolism*
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Apolipoprotein A-I / ultrastructure
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Atherosclerosis / metabolism*
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Benzothiazoles
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CHO Cells
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Cholesterol / metabolism
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Cricetinae
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Cricetulus
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Heparin / metabolism
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Humans
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Hydrogen-Ion Concentration / drug effects
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Hypochlorous Acid / pharmacology
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Matrix Metalloproteinase 12 / metabolism
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Neutrophil Activation / drug effects
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Oxidation-Reduction / drug effects
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Protein Binding / drug effects
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Protein Folding / drug effects
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Protein Stability / drug effects
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Protein Structure, Quaternary
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Protein Structure, Secondary
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Proteolysis / drug effects
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Solvents
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Tetradecanoylphorbol Acetate / pharmacology
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Thiazoles / metabolism
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Tryptophan / metabolism
Substances
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APOA1 protein, human
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Amyloid
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Anilino Naphthalenesulfonates
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Apolipoprotein A-I
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Benzothiazoles
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Solvents
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Thiazoles
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thioflavin T
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5,5'-bis(8-(phenylamino)-1-naphthalenesulfonate)
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Hypochlorous Acid
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Tryptophan
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Heparin
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Cholesterol
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Matrix Metalloproteinase 12
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Tetradecanoylphorbol Acetate