title: Acrolein impairs ATP binding cassette transporter A1-dependent cholesterol export from cells through site-specific modification of apolipoprotein A-I.
abstract: Acrolein is a highly reactive alpha,beta-unsaturated aldehyde, but the factors that control its reactions with nucleophilic groups on proteins remain poorly understood. Lipid peroxidation and threonine oxidation by myeloperoxidase are potential sources of acrolein during inflammation. Because both pathways are implicated in atherogenesis and high density lipoprotein (HDL) is anti-atherogenic, we investigated the possibility that acrolein might target the major protein of HDL, apolipoprotein A-I (apoA-I), for modification. Tandem mass spectrometric analysis demonstrated that lysine 226, located near the center of helix 10 in apoA-I, was the major site modified by acrolein. Importantly, this region plays a critical role in the cellular interactions and ability of apoA-I to transport lipid. Indeed, we found that conversion of Lys-226 to N(epsilon)-(3-methylpyridinium)lysine by acrolein associated quantitatively with decreased cholesterol efflux from cells via the ATP-binding cassette transporter A1 pathway. In the crystal structure of truncated apoA-I, Glu-234 lies adjacent to Lys-226, suggesting that negatively charged residues might direct the modification of specific lysine residues in proteins. Finally, immunohistochemical studies with a monoclonal antibody revealed co-localization of apoA-I with acrolein adducts in human atherosclerotic lesions. Our observations suggest that acrolein might interfere with normal reverse cholesterol transport by HDL by modifying specific sites in apoA-I. Thus, acrolein might contribute to atherogenesis by impairing cholesterol removal from the artery wall.
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Baohai
authors.initials: B
authors.lastname: Shao
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Fu
authors.forename: Thomas O
authors.initials: TO
authors.lastname: McDonald
authors.forename: Pattie S
authors.initials: PS
authors.lastname: Green
authors.forename: Koji
authors.initials: K
authors.lastname: Uchida
authors.forename: Kevin D
authors.initials: KD
authors.lastname: O'Brien
authors.forename: John F
authors.initials: JF
authors.lastname: Oram
authors.forename: Jay W
authors.initials: JW
authors.lastname: Heinecke
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000171:Acrolein / Q000737:chemistry*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000737:chemistry; D016632:Apolipoprotein A-I / Q000737:chemistry* / Q000378:metabolism; D001158:Arteries / Q000473:pathology; D050197:Atherosclerosis / Q000473:pathology; D015153:Blotting, Western; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism*; D002853:Chromatography, Liquid; D018360:Crystallography, X-Ray; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation; D015227:Lipid Peroxidation; D008075:Lipoproteins, HDL / Q000737:chemistry; D008239:Lysine / Q000737:chemistry; D013058:Mass Spectrometry; D008956:Models, Chemical; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D009195:Peroxidase / Q000378:metabolism; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid; D021241:Spectrometry, Mass, Electrospray Ionization; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013696:Temperature; D013912:Threonine / Q000737:chemistry; D013997:Time Factors
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000911:Antibodies, Monoclonal; D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D010455:Peptides; D010743:Phospholipids; D013912:Threonine; D000171:Acrolein; D000255:Adenosine Triphosphate; D002784:Cholesterol; D009195:Peroxidase; D008239:Lysine