An Abundant Dysfunctional Apolipoprotein A1 in Human Atheroma
What makes high-density lipoprotein (HDL) go bad?
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.
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.
The authors concluded that circulating oxTrp72-apoA1 levels may serve as a way to monitor a proatherogenic process in the artery wall.
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.
Keywords: Cholesterol, Mutagenesis, Atherosclerosis, Plaque, Atherosclerotic, ATP-Binding Cassette Transporters, Apolipoprotein A-I, Cardiovascular Diseases, Cell Surface Display Techniques
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