An abundant dysfunctional apolipoprotein A1 in human atheroma
| Autor: | Jennie E. Hazen, Joseph A. DiDonato, Valentin Gogonea, Leslie Cho, Timothy Kim, W.H. Wilson Tang, Stanley L. Hazen, Anthony J. DiDonato, Edward A. Fisher, Yuping Wu, Jennifer A. Buffa, Dao-Quan Peng, Zeneng Wang, Jonathan D. Smith, Xiaoming Fu, Chandra S Kadiyala, Truc Nguyen, Dave Schmitt, John S. Parks, Paul L. Fox, Xiaodong Gu, Miranda K. Culley, Bruce S. Levison, Edward F. Plow, Ying Huang, Lin Li, Gary Gerstenecker, Stela Z Berisha, Chia-Chi Chuang, Shaohong Liang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
medicine.medical_specialty
Apolipoprotein B Fluorescent Antibody Technique Vascular Cell Adhesion Molecule-1 Dysfunctional family Enzyme-Linked Immunosorbent Assay 030204 cardiovascular system & hematology General Biochemistry Genetics and Molecular Biology Article Coronary artery disease 03 medical and health sciences chemistry.chemical_compound Epitopes 0302 clinical medicine Tandem Mass Spectrometry Internal medicine medicine Odds Ratio Humans 030304 developmental biology Peroxidase 0303 health sciences Alanine biology Apolipoprotein A-I Cholesterol nutritional and metabolic diseases Antibodies Monoclonal General Medicine medicine.disease Immunohistochemistry Plaque Atherosclerotic 3. Good health Oxindoles Endocrinology Atheroma chemistry Cardiovascular Diseases Mutagenesis Immunology biology.protein Apolipoprotein A1 lipids (amino acids peptides and proteins) Cell Surface Display Techniques Lipoproteins HDL Oxidation-Reduction Lipoprotein Chromatography Liquid |
| Zdroj: | Nature medicine |
| ISSN: | 1546-170X 1078-8956 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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