title: Oxidation of low-density lipoproteins induces amyloid-like structures that are recognized by macrophages.
abstract: The macrophage scavenger receptor CD36 plays a key role in the initiation of atherosclerosis through its ability to bind to and internalize oxidized low-density lipoproteins (oxLDL). Prompted by recent findings that the CD36 receptor also recognizes amyloid fibrils formed by beta-amyloid and apolipoprotein C-II, we investigated whether the oxidation of low-density lipoproteins (LDL) generates characteristic amyloid-like structures and whether these structures serve as CD36 ligands. Our studies demonstrate that LDL oxidized by copper ions, 2,2-azobis(2-amidinopropane) dihydrochloride (AAPH), or ozone react with the diagnostic amyloid dyes thioflavin T and Congo Red and bind to serum amyloid P component (SAP), a universal constituent of physiological amyloid deposits. X-ray powder diffraction patterns for native LDL show a diffuse powder diffraction ring with maximum intensity corresponding to an atomic spacing of approximately 4.7 A, consistent with the spacing between beta-strands in a beta-sheet. Ozone treatment of LDL generates an additional diffuse powder diffraction ring with maximum intensity indicating a spacing of approximately 9.8 A. This distance is consistent with the presence of cross-beta-structure, a defining characteristic of amyloid. Evidence that these cross-beta-amyloid structures in oxLDL are recognized by macrophages is provided by the observation that SAP strongly inhibits the association and internalization of (125)I-labeled copper-oxidized LDL by peritoneal macrophages. The ability of SAP to bind to amyloid-like structures in oxLDL and prevent lipid uptake by macrophages highlights the potential importance of these structures and suggests an important preventative role for SAP in foam cell formation and early-stage atherosclerosis.
authors.affiliation: Russell Grimwade School of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Cameron R
authors.initials: CR
authors.lastname: Stewart
authors.forename: Anita A
authors.initials: AA
authors.lastname: Tseng
authors.forename: Yee-Foong
authors.initials: YF
authors.lastname: Mok
authors.forename: Maree K
authors.initials: MK
authors.lastname: Staples
authors.forename: Carl H
authors.initials: CH
authors.lastname: Schiesser
authors.forename: Lynne J
authors.initials: LJ
authors.lastname: Lawrence
authors.forename: Jose N
authors.initials: JN
authors.lastname: Varghese
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Moore
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Howlett
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D052160:Benzothiazoles; D002478:Cells, Cultured; D002850:Chromatography, Gel; D003224:Congo Red / Q000737:chemistry; D006801:Humans; D008077:Lipoproteins, LDL / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism*; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D046529:Microscopy, Electron, Transmission; D010084:Oxidation-Reduction / Q000187:drug effects; D013050:Spectrometry, Fluorescence; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism; D014961:X-Ray Diffraction
chemical_list: D000682:Amyloid; D052160:Benzothiazoles; D008077:Lipoproteins, LDL; D013844:Thiazoles; C099252:oxidized low density lipoprotein; C009462:thioflavin T; D003224:Congo Red