An abundant dysfunctional apolipoprotein A1 in human atheroma.

Abstract

Recent studies have indicated that high-density lipoproteins (HDLs) and their major structural protein, apolipoprotein A1 (apoA1), recovered from human atheroma are dysfunctional and are extensively oxidized by myeloperoxidase (MPO). In vitro oxidation of either apoA1 or HDL particles by MPO impairs their cholesterol acceptor function. Here, using phage display affinity maturation, we developed a high-affinity monoclonal antibody that specifically recognizes both apoA1 and HDL that have been modified by the MPO-H2O2-Cl(-) system. An oxindolyl alanine (2-OH-Trp) moiety at Trp72 of apoA1 is the immunogenic epitope. Mutagenesis studies confirmed a critical role for apoA1 Trp72 in MPO-mediated inhibition of the ATP-binding cassette transporter A1 (ABCA1)-dependent cholesterol acceptor activity of apoA1 in vitro and in vivo. ApoA1 containing a 2-OH-Trp72 group (oxTrp72-apoA1) is in low abundance within the circulation but accounts for 20% of the apoA1 in atherosclerosis-laden arteries. OxTrp72-apoA1 recovered from human atheroma or plasma is lipid poor, virtually devoid of cholesterol acceptor activity and demonstrated both a potent proinflammatory activity on endothelial cells and an impaired HDL biogenesis activity in vivo. Elevated oxTrp72-apoA1 levels in subjects presenting to a cardiology clinic (n = 627) were associated with increased cardiovascular disease risk. Circulating oxTrp72-apoA1 levels may serve as a way to monitor a proatherogenic process in the artery wall.

• Authors: Ying Huang, Joseph A DiDonato, Bruce S Levison, Dave Schmitt, Lin Li, Yuping Wu, Jennifer Buffa, Timothy Kim, Gary S Gerstenecker, Xiaodong Gu, Chandra S Kadiyala, Zeneng Wang, Miranda K Culley, Jennie E Hazen, Anthony J Didonato, Xiaoming Fu, Stela Z Berisha, Daoquan Peng, Truc T Nguyen, Shaohong Liang, Chia-Chi Chuang, Leslie Cho, Edward F Plow, Paul L Fox, Valentin Gogonea, W H Wilson Tang, John S Parks, Edward A Fisher, Jonathan D Smith, Stanley L Hazen
• Journal: Nature medicine (Nat Med) Vol. 20 Issue 2 Pg. 193-203 (Feb 2014) ISSN: 1546-170X [Electronic] United States
• PMID: 24464187 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Apolipoprotein A-I
• Epitopes
• Lipoproteins, HDL
• Oxindoles
• Vascular Cell Adhesion Molecule-1
• oxindolylalanine
• Peroxidase
• Alanine

Topics

• Alanine (analogs & derivatives, genetics)
• Antibodies, Monoclonal
• Apolipoprotein A-I (genetics, immunology, metabolism)
• Cardiovascular Diseases (genetics)
• Cell Surface Display Techniques
• Chromatography, Liquid
• Enzyme-Linked Immunosorbent Assay
• Epitopes (genetics)
• Fluorescent Antibody Technique
• Humans
• Immunohistochemistry
• Lipoproteins, HDL (immunology, metabolism)
• Mutagenesis
• Odds Ratio
• Oxidation-Reduction
• Oxindoles
• Peroxidase (metabolism)
• Plaque, Atherosclerotic (genetics, metabolism)
• Tandem Mass Spectrometry
• Vascular Cell Adhesion Molecule-1 (metabolism)