title: Impact of HDL oxidation by the myeloperoxidase system on sterol efflux by the ABCA1 pathway.
abstract: Protein oxidation by phagocytic white blood cells is implicated in tissue injury during inflammation. One important target might be high-density lipoprotein (HDL), which protects against atherosclerosis by removing excess cholesterol from artery wall macrophages. In the human artery wall, cholesterol-laden macrophages are a rich source of myeloperoxidase (MPO), which uses hydrogen peroxide for oxidative reactions in the extracellular milieu. Levels of two characteristic products of MPO-chlorotyrosine and nitrotyrosine-are markedly elevated in HDL from human atherosclerotic lesions. Here, we describe how MPO-dependent chlorination impairs the ability of apolipoprotein A-I (apoA-I), HDL's major protein, to transport cholesterol by the ATP-binding cassette transporter A1 (ABCA1) pathway. Faulty interactions between apoA-I and ABCA1 are involved. Tandem mass spectrometry and investigations of mutated forms of apoA-I demonstrate that tyrosine residues in apoA-I are chlorinated in a site-specific manner by chloramine intermediates on suitably juxtaposed lysine residues. Plasma HDL isolated from subjects with coronary artery disease (CAD) also contains higher levels of chlorinated and nitrated tyrosine residues than HDL from healthy subjects. Thus, the presence of chlorinated HDL might serve as a marker of CAD risk. Because HDL damaged by MPO in vitro becomes dysfunctional, inhibiting MPO in vivo might be cardioprotective.
authors.affiliation: Division of Metabolism, Endocrinology and Nutrition, Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, WA 98109, USA. bhshao@u.washington.edu
authors.forename: Baohai
authors.initials: B
authors.lastname: Shao
authors.forename: Jay W
authors.initials: JW
authors.lastname: Heinecke
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism*; D053858:Metabolic Networks and Pathways / Q000235:genetics / Q000502:physiology; D008954:Models, Biological; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000378:metabolism / Q000502:physiology*; D013261:Sterols / Q000378:metabolism*
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008075:Lipoproteins, HDL; D013261:Sterols; D009195:Peroxidase