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Updated: May 2, 2026
Quantification of Atherosclerosis in Mice
Published on: June 12, 2019
Humans with atherosclerosis have impaired ABCA1 cholesterol efflux and enhanced high-density lipoprotein oxidation by
Baohai Shao1, Chongren Tang2, Abhishek Sinha2
1From 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.
Insights
Myeloperoxidase (MPO) causes oxidative damage to apolipoprotein A-I in high-density lipoprotein (HDL), impairing cholesterol efflux. This dysfunction is linked to cardiovascular disease and may serve as an independent risk indicator.
Area of Science:
- Cardiovascular Research
- Lipid Metabolism
- Oxidative Stress
Background:
- Impaired high-density lipoprotein (HDL) cholesterol efflux capacity is linked to coronary artery disease (CAD).
- Mechanisms underlying reduced HDL sterol efflux capacity are not fully understood.
Purpose of the Study:
- To investigate the relationship between myeloperoxidase-mediated oxidative damage to apolipoprotein A-I (apoA-I) and HDL's cholesterol efflux capacity via the ATP-binding cassette transporter A1 (ABCA1) pathway.
Main Methods:
- Quantified site-specific oxidation of apoA-I (chlorotyrosine, oxidized methionine) and HDL's ABCA1 cholesterol efflux capacity.
- Compared these measures in control subjects, patients with stable CAD, and patients with acute coronary syndrome.
Main Results:
- Subjects with CAD exhibited higher levels of chlorinated tyrosine 192 and oxidized methionine 148 in HDL.
- HDL from CAD patients showed reduced cholesterol efflux capacity via ABCA1.
- Oxidized apoA-I levels correlated inversely with efflux capacity and positively with CAD status, independent of HDL-cholesterol levels.
Conclusions:
- Myeloperoxidase (MPO) may generate dysfunctional HDL with impaired ABCA1 efflux capacity in atherosclerosis.
- Quantification of specific HDL oxidative modifications (chlorotyrosine, oxidized methionine) may serve as novel cardiovascular disease risk biomarkers.
Rationale:
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.
Methods And 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.
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