title: Humans with atherosclerosis have impaired ABCA1 cholesterol efflux and enhanced high-density lipoprotein oxidation by myeloperoxidase.
abstract: BACKGROUND
  The efflux capacity of high-density lipoprotein (HDL) with cultured macrophages associates strongly and negatively with coronary artery disease status, indicating that impaired sterol efflux capacity might be a marker-and perhaps mediator-of atherosclerotic burden. However, the mechanisms that contribute to impaired sterol efflux capacity remain poorly understood.
  
  
  OBJECTIVE
  Our aim was to determine the relationship between myeloperoxidase-mediated oxidative damage to apolipoprotein A-I, the major HDL protein, and the ability of HDL to remove cellular cholesterol by the ATP-binding cassette transporter A1 (ABCA1) pathway.
  
  
  RESULTS
  We quantified both site-specific oxidation of apolipoprotein A-I and HDL's ABCA1 cholesterol efflux capacity in control subjects and subjects with stable coronary artery disease or acute coronary syndrome. Subjects with coronary artery disease and acute coronary syndrome had higher levels of chlorinated tyrosine 192 and oxidized methionine 148 compared with control subjects. In contrast, plasma levels of myeloperoxidase did not differ between the groups. HDL from the subjects with coronary artery disease and acute coronary syndrome was less able to accept cholesterol from cells expressing ABCA1 compared with HDL from control subjects. Levels of chlorinated tyrosine and oxidized methionine associated inversely with ABCA1 efflux capacity and positively with atherosclerotic disease status. These differences remained significant after adjusting for HDL-cholesterol levels.
  
  
  CONCLUSIONS
  Our observations indicate that myeloperoxidase may contribute to the generation of dysfunctional HDL with impaired ABCA1 efflux capacity in humans with atherosclerosis. Quantification of chlorotyrosine and oxidized methionine in circulating HDL might be useful indicators of the risk of cardiovascular disease that are independent of HDL-cholesterol.
authors.affiliation: From the Department of Medicine, University of Washington, Seattle (B.S., C.T., A.S., P.S.M., G.D.D., X.-Q.Z., J.W.H.); Diabetes and Obesity Center of Excellence, University of Washington, Seattle (B.S, C.T., P.S.M., J.W.H.); Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY (N.B.); Center for Molecular Biology and Biotechnology, Florida Atlantic University, Jupiter (N.B.); and Children's Hospital Oakland Research Institute, CA (M.N.O.). bhshao@u.washington.edu.
authors.forename: Baohai
authors.initials: B
authors.lastname: Shao
authors.affiliation: From the Department of Medicine, University of Washington, Seattle (B.S., C.T., A.S., P.S.M., G.D.D., X.-Q.Z., J.W.H.); Diabetes and Obesity Center of Excellence, University of Washington, Seattle (B.S, C.T., P.S.M., J.W.H.); Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY (N.B.); Center for Molecular Biology and Biotechnology, Florida Atlantic University, Jupiter (N.B.); and Children's Hospital Oakland Research Institute, CA (M.N.O.).
authors.forename: Chongren
authors.initials: C
authors.lastname: Tang
authors.affiliation: From the Department of Medicine, University of Washington, Seattle (B.S., C.T., A.S., P.S.M., G.D.D., X.-Q.Z., J.W.H.); Diabetes and Obesity Center of Excellence, University of Washington, Seattle (B.S, C.T., P.S.M., J.W.H.); Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY (N.B.); Center for Molecular Biology and Biotechnology, Florida Atlantic University, Jupiter (N.B.); and Children's Hospital Oakland Research Institute, CA (M.N.O.).
authors.forename: Abhishek
authors.initials: A
authors.lastname: Sinha
authors.affiliation: From the Department of Medicine, University of Washington, Seattle (B.S., C.T., A.S., P.S.M., G.D.D., X.-Q.Z., J.W.H.); Diabetes and Obesity Center of Excellence, University of Washington, Seattle (B.S, C.T., P.S.M., J.W.H.); Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY (N.B.); Center for Molecular Biology and Biotechnology, Florida Atlantic University, Jupiter (N.B.); and Children's Hospital Oakland Research Institute, CA (M.N.O.).
authors.forename: Philip S
authors.initials: PS
authors.lastname: Mayer
authors.affiliation: From the Department of Medicine, University of Washington, Seattle (B.S., C.T., A.S., P.S.M., G.D.D., X.-Q.Z., J.W.H.); Diabetes and Obesity Center of Excellence, University of Washington, Seattle (B.S, C.T., P.S.M., J.W.H.); Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY (N.B.); Center for Molecular Biology and Biotechnology, Florida Atlantic University, Jupiter (N.B.); and Children's Hospital Oakland Research Institute, CA (M.N.O.).
authors.forename: George D
authors.initials: GD
authors.lastname: Davenport
authors.affiliation: From the Department of Medicine, University of Washington, Seattle (B.S., C.T., A.S., P.S.M., G.D.D., X.-Q.Z., J.W.H.); Diabetes and Obesity Center of Excellence, University of Washington, Seattle (B.S, C.T., P.S.M., J.W.H.); Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY (N.B.); Center for Molecular Biology and Biotechnology, Florida Atlantic University, Jupiter (N.B.); and Children's Hospital Oakland Research Institute, CA (M.N.O.).
authors.forename: Nathan
authors.initials: N
authors.lastname: Brot
authors.affiliation: From the Department of Medicine, University of Washington, Seattle (B.S., C.T., A.S., P.S.M., G.D.D., X.-Q.Z., J.W.H.); Diabetes and Obesity Center of Excellence, University of Washington, Seattle (B.S, C.T., P.S.M., J.W.H.); Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY (N.B.); Center for Molecular Biology and Biotechnology, Florida Atlantic University, Jupiter (N.B.); and Children's Hospital Oakland Research Institute, CA (M.N.O.).
authors.forename: Michael N
authors.initials: MN
authors.lastname: Oda
authors.affiliation: From the Department of Medicine, University of Washington, Seattle (B.S., C.T., A.S., P.S.M., G.D.D., X.-Q.Z., J.W.H.); Diabetes and Obesity Center of Excellence, University of Washington, Seattle (B.S, C.T., P.S.M., J.W.H.); Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY (N.B.); Center for Molecular Biology and Biotechnology, Florida Atlantic University, Jupiter (N.B.); and Children's Hospital Oakland Research Institute, CA (M.N.O.).
authors.forename: Xue-Qiao
authors.initials: XQ
authors.lastname: Zhao
authors.affiliation: From the Department of Medicine, University of Washington, Seattle (B.S., C.T., A.S., P.S.M., G.D.D., X.-Q.Z., J.W.H.); Diabetes and Obesity Center of Excellence, University of Washington, Seattle (B.S, C.T., P.S.M., J.W.H.); Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY (N.B.); Center for Molecular Biology and Biotechnology, Florida Atlantic University, Jupiter (N.B.); and Children's Hospital Oakland Research Institute, CA (M.N.O.).
authors.forename: Jay W
authors.initials: JW
authors.lastname: Heinecke
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism*; D054058:Acute Coronary Syndrome / Q000378:metabolism / Q000503:physiopathology; D000368:Aged; D016632:Apolipoprotein A-I / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism* / Q000503:physiopathology; D015415:Biomarkers / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D003324:Coronary Artery Disease / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008297:Male; D008715:Methionine / Q000378:metabolism; D008875:Middle Aged; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D016632:Apolipoprotein A-I; D015415:Biomarkers; D008075:Lipoproteins, HDL; D002097:C-Reactive Protein; D002784:Cholesterol; D008715:Methionine; D009195:Peroxidase
keywords: 3-chlorotyrosine; acute coronary syndrome; cardiovascular diseases; mass spectrometry; peroxidase