A key cardioprotective effect of
high-density lipoprotein involves the interaction of its major
protein,
apolipoprotein A-I (
apoA-I) with
ATP-binding cassette transporter A1 (ABCA1), a macrophage
cholesterol exporter.
ApoA-I is thought to remove
cholesterol from macrophages by a cascade of events. First it binds directly to ABCA1, activating signaling pathways, and then it binds to and solubilizes
lipid domains generated by ABCA1. HDL isolated from human atherosclerotic lesions and blood of subjects with established
coronary artery disease contains elevated levels of
3-chlorotyrosine and
3-nitrotyrosine, two characteristic products of
myeloperoxidase (MPO), a
heme protein secreted by macrophages. Here we show that chlorination (but not nitration) of
apoA-I by the MPO pathway impairs its ability to interact directly with ABCA1, to activate the
Janus kinase 2 signaling pathway, and to promote efflux of cellular
cholesterol. In contrast, oxidation of
apoA-I has little effect on its ability to stabilize
ABCA1 protein or to solubilize
phospholipids. Our results indicate that chlorination of
apoA-I by the MPO pathway selectively inhibits two critical early events in
cholesterol efflux: (1) the binding of
apoA-I to ABCA1 and (2) the activation of a key signaling pathway. Therefore, oxidation of
apoA-I in the artery wall by MPO-generated chlorinating intermediates may contribute to
atherogenesis by impairing
cholesterol efflux from macrophages.