title: Myeloperoxidase-mediated Methionine Oxidation Promotes an Amyloidogenic Outcome for Apolipoprotein A-I.
abstract: High plasma levels of apolipoprotein A-I (apoA-I) correlate with cardiovascular health, whereas dysfunctional apoA-I is a cause of atherosclerosis. In the atherosclerotic plaques, amyloid deposition increases with aging. Notably, apoA-I is the main component of these amyloids. Recent studies identified high levels of oxidized lipid-free apoA-I in atherosclerotic plaques. Likely, myeloperoxidase (MPO) secreted by activated macrophages in atherosclerotic lesions is the promoter of such apoA-I oxidation. We hypothesized that apoA-I oxidation by MPO levels similar to those present in the artery walls in atherosclerosis can promote apoA-I structural changes and amyloid fibril formation. ApoA-I was exposed to exhaustive chemical (H2O2) oxidation or physiological levels of enzymatic (MPO) oxidation and incubated at 37 °C and pH 6.0 to induce fibril formation. Both chemically and enzymatically oxidized apoA-I produced fibrillar amyloids after a few hours of incubation. The amyloid fibrils were composed of full-length apoA-I with differential oxidation of the three methionines. Met to Leu apoA-I variants were used to establish the predominant role of oxidation of Met-86 and Met-148 in the fibril formation process. Importantly, a small amount of preformed apoA-I fibrils was able to seed amyloid formation in oxidized apoA-I at pH 7.0. In contrast to hereditary amyloidosis, wherein specific mutations of apoA-I cause protein destabilization and amyloid deposition, oxidative conditions similar to those promoted by local inflammation in atherosclerosis are sufficient to transform full-length wild-type apoA-I into an amyloidogenic protein. Thus, MPO-mediated oxidation may be implicated in the mechanism that leads to amyloid deposition in the atherosclerotic plaques in vivo.
authors.affiliation: From the Children's Hospital Oakland Research Institute, Oakland, California 94609.
authors.forename: Gary K L
authors.initials: GK
authors.lastname: Chan
authors.affiliation: From the Children's Hospital Oakland Research Institute, Oakland, California 94609.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Witkowski
authors.affiliation: Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts 02118, and.
authors.forename: Donald L
authors.initials: DL
authors.lastname: Gantz
authors.affiliation: Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706.
authors.forename: Tianqi O
authors.initials: TO
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706.
authors.forename: Martin T
authors.initials: MT
authors.lastname: Zanni
authors.affiliation: Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts 02118, and.
authors.forename: Shobini
authors.initials: S
authors.lastname: Jayaraman
authors.affiliation: From the Children's Hospital Oakland Research Institute, Oakland, California 94609, gcavigiolio@chori.org.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Cavigiolio
mesh_terms: D000682:Amyloid / Q000235:genetics / Q000378:metabolism*; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D008715:Methionine / Q000235:genetics / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism*; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C505693:APOA1 protein, human; D000682:Amyloid; D016632:Apolipoprotein A-I; D016877:Oxidants; D008715:Methionine; D006861:Hydrogen Peroxide; D009195:Peroxidase
keywords: 2D (Two-dimensional) Infrared Spectroscopy; Amyloid; Amyloidosis; Apolipoprotein; Apolipoprotein A-I; Atherosclerosis; Fibril; Myeloperoxidase; Oxidation