An abundant dysfunctional apolipoprotein A1 in human atheroma

Abstract

Recent studies indicate high density lipoproteins (HDL) and their major structural protein, apolipoprotein A1 (apoA1), recovered from human atheroma, are dysfunctional and extensively oxidized by myeloperoxidase (MPO), while in vitro oxidation of apoA1/HDL by MPO impairs its cholesterol acceptor function. We developed a high affinity monoclonal antibody (mAb) that specifically recognizes apoA1/HDL modified by the MPO/H2O2/Cl-system using phage display affinity maturation. An oxindolyl alanine (2-OH-Trp) moiety at tryptophan 72 of apoA1 is the immunogenic epitope. Mutagenesis studies confirm a critical role for apoA1 Trp72 in MPO-mediated inhibition of 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 atherosclerotic plaque. OxTrp72-apoA1 recovered from human atheroma or plasma was lipid-poor, virtually devoid of cholesterol acceptor activity, and demonstrated both potent pro-inflammatory activities 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 cardiovascular disease risk. Circulating oxTrp72-apoA1 levels may serve as a way to monitor a pro-atherogenic process in the artery wall.

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

“…135 Also, apoA-I with oxidative modification of the tryptophan residue Trp-72, a form of apoA-I that is highly prevalent in apoA-I recovered from atheroma and increased in the plasma of patients with cardiovascular disease or CAD, had significantly lower cholesterol acceptor capacity. 131 Mechanistically, MPO-dependent chlorination of apoA-I interfered with the binding of apoA-I to ABCA1 and as a consequence chlorinated apoA-I failed to activate the accompanying JAK2 signaling. 132 However, it must be noted that in plasma less than 200 of 1 million apoA-I molecules contain oxidized Tyr-192 or Trp-72 residues.…”

“…132 However, it must be noted that in plasma less than 200 of 1 million apoA-I molecules contain oxidized Tyr-192 or Trp-72 residues. 129, 131 In view of their very low quantity it is unlikely that these modifications reduce cholesterol efflux capacity of (apoB-free) plasma or HDL by simple loss-of-function in the interaction with ABCA1. Rather additional gain of dysfunction is necessary to explain reduced ABCA1-mediated cholesterol efflux capacity of plasma by these modifications.…”

“…41 Likewise, differences in cholesterol efflux capacity have been attributed to differences in HDL particle number, HDL subclass distribution, phospholipid composition, 86 the presence of SAA, 58-61 or posttranslational modifications. [127][128][129][130][131][132] As yet it is not clear whether these findings reflect redundancy or complexity of HDL interactions with endothelial cells or result from confounding.…”

ApoA1 and ApoA1-specific self-antibodies in cardiovascular disease

“…76 MPO-mediated oxidation of Trp 72 leads to the formation of the oxTrp72-ApoA1 variant that is abundantly present (20% of total apoA1 in atherosclerotic vessels) in the plaque and lack an ability to activate ABCA1. 77 MPO-dependent nitration and chlorination of ApoA1 at Tyr 192 along with methionine oxidation results in a loss of ability to activate RCT. 78,79 Modified ApoA1 form HDL with impaired function.…”

“…The 2-OH-Trp moiety is the immunogenic epitope recognized by a high-affinity monoclonal antibody that is also capable to bind to HDL treated with MPO. 77 Recently, Teixeira et al 83 found two novel immunoreactive peptides recognizable by self-antibodies from MI patients with higher titers of ApoA1 IgG. The first peptide (peptide C) comprises 28 residues (Gln 240 -Gln 267 ) and includes a whole non-polar α-helix involved in lipid solubilization.…”