An abundant dysfunctional apolipoprotein A1 in human atheroma.
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.
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
Ying
Y
Huang
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
Joseph A
JA
DiDonato
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
Bruce S
BS
Levison
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
Dave
D
Schmitt
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
Lin
L
Li
Department of Mathematics, Cleveland State University, Cleveland, Ohio, USA.
Yuping
Y
Wu
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
Jennifer
J
Buffa
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
Timothy
T
Kim
1] Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA. [2] Department of Chemistry, Cleveland State University, Cleveland, Ohio, USA.
Gary S
GS
Gerstenecker
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
Xiaodong
X
Gu
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
Chandra S
CS
Kadiyala
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
Zeneng
Z
Wang
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
Miranda K
MK
Culley
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
Jennie E
JE
Hazen
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
Anthony J
AJ
Didonato
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
Xiaoming
X
Fu
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
Stela Z
SZ
Berisha
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
Daoquan
D
Peng
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
Truc T
TT
Nguyen
Cleveland Heart Lab, Cleveland, Ohio, USA.
Shaohong
S
Liang
Department of Pathology, Section on Lipid Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
Chia-Chi
CC
Chuang
1] Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA. [2] Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
Leslie
L
Cho
1] Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, USA. [2] Department of Molecular Cardiology, Cleveland Clinic, Cleveland, Ohio, USA.
Edward F
EF
Plow
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
Paul L
PL
Fox
1] Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA. [2] Department of Chemistry, Cleveland State University, Cleveland, Ohio, USA.
Valentin
V
Gogonea
1] Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA. [2] Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
W H Wilson
WH
Tang
1] Department of Pathology, Section on Lipid Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. [2] Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
John S
JS
Parks
Department of Cardiovascular Medicine, New York University School of Medicine, New York, New York, USA.
Edward A
EA
Fisher
1] Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA. [2] Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
Jonathan D
JD
Smith
1] Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA. [2] Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
Stanley L
SL
Hazen
D000409:Alanine / Q000031:analogs & derivatives / Q000235:genetics; D000911:Antibodies, Monoclonal; D016632:Apolipoprotein A-I / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000235:genetics*; D061505:Cell Surface Display Techniques; D002853:Chromatography, Liquid; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000235:genetics; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008075:Lipoproteins, HDL / Q000276:immunology / Q000378:metabolism*; D016296:Mutagenesis; D016017:Odds Ratio; D010084:Oxidation-Reduction; D000078183:Oxindoles; D009195:Peroxidase / Q000378:metabolism*; D058226:Plaque, Atherosclerotic / Q000235:genetics* / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D000911:Antibodies, Monoclonal; D016632:Apolipoprotein A-I; D000939:Epitopes; D008075:Lipoproteins, HDL; D000078183:Oxindoles; D019010:Vascular Cell Adhesion Molecule-1; C044832:oxindolylalanine; D009195:Peroxidase; D000409:Alanine