title: Pathways for oxidation of high-density lipoprotein in human cardiovascular disease.
abstract: The cardioprotective effect of high-density lipoprotein (HDL) is thought to involve, in part, the membrane-associated ATP-binding cassette transporter ABCA1, which clears cholesterol from lipid-laden macrophages in the artery wall. If HDL is unable to interact with this transporter because of oxidative damage, cholesterol clearance is impaired. Important insights into the mechanisms that oxidize proteins in the human artery wall have come from the mass spectrometric (MS) detection of oxidized amino acids that result from specific reaction pathways. Recent MS studies indicate that HDL isolated from patients with cardiovascular disease contains elevated levels of 3-chlorotyrosine and 3-nitrotyrosine, which are two characteristic products of myeloperoxidase (MPO), a heme enzyme secreted by macrophages. MPO-dependent chlorination of apolipoprotein A-I (apoA-I), the major HDL protein, impairs its ability to remove excess cellular cholesterol by the ABCA1 pathway. Tandem MS analysis of apoA-I has demonstrated that this loss of activity is associated with methionine oxidation and chlorination of a single tyrosine residue. Analysis of mutated forms of apoA-I has implicated lysine residues in the regiospecific chlorination of tyrosine. It is further suggested that the tyrosine chlorination and methionine oxidation of apoA-I impairs ABCA1 transport activity. The crystal structure of lipid-free apoA-I suggests a potential mechanism for rendering this protein dysfunctional. Collectively, these observations indicate that MPO oxidatively damages HDL in humans and suggest that oxidation of specific amino acid residues in apoA-I may contribute to atherogenesis by impairing cholesterol efflux from macrophages.
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Baohai
authors.initials: B
authors.lastname: Shao
authors.forename: Michael N
authors.initials: MN
authors.lastname: Oda
authors.forename: Tomas
authors.initials: T
authors.lastname: Vaisar
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; D016632:Apolipoprotein A-I / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000378:metabolism*; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism*; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000378:metabolism
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D009195:Peroxidase