An Abundant Dysfunctional Apolipoprotein A1 in Human Atheroma

Study Questions:

What makes high-density lipoprotein (HDL) go bad?

Methods:

Using phage display techniques, a high-affinity monoclonal antibody was developed that specifically recognizes both apolipoprotein A1 (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.

Results:

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 impaired HDL biogenesis activity in vivo. Elevated oxTrp72-apoA1 levels in subjects presenting to a cardiology clinic (n = 627) were associated with increased risk of cardiovascular disease.

Conclusions:

The authors concluded that circulating oxTrp72-apoA1 levels may serve as a way to monitor a proatherogenic process in the artery wall.

Perspective:

Multiple clinical trials of therapeutic interventions designed to raise HDL and reduce cardiovascular risk have failed, despite numerous preclinical studies suggesting atheroprotective effects of HDL. A possible explanation for this discrepancy is that there is heterogeneity of HDL particles with both pro- and anti-inflammatory effects. A greater understanding of HDL biology is needed to guide future interventions. This study demonstrates a mechanism by which HDL is modified to become a proinflammatory particle. In addition to identification of a new biomarker reflective of dysfunction HDL, these results indicate that reduction of MPO activity may have beneficial effects toward preserving atheroprotective properties of HDL.

Clinical Topics: Dyslipidemia, Lipid Metabolism, Nonstatins

Keywords: Cholesterol, Mutagenesis, Atherosclerosis, Plaque, Atherosclerotic, ATP-Binding Cassette Transporters, Apolipoprotein A-I, Cardiovascular Diseases, Cell Surface Display Techniques


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