High density lipoprotein (HDL) is the major atheroprotective particle in plasma. Recent studies demonstrate that
myeloperoxidase (MPO) binds to HDL in vivo, selectively targeting
apolipoprotein A1 (apoA1) of HDL for oxidative modification and concurrent loss in
cholesterol efflux and
lecithin cholesterol acyl
transferase activating activities, generating a "dysfunctional HDL" particle. We now show that (patho)physiologically relevant levels of MPO-catalyzed oxidation result in loss of non-
cholesterol efflux activities of HDL including anti-apoptotic and anti-inflammatory functions. One mechanism responsible is shown to involve the loss of modified HDL binding to the
HDL receptor,
scavenger receptor B1, and concurrent acquisition of saturable and specific binding to a novel unknown receptor independent of
scavenger receptors CD36 and SR-A1. HDL modification by MPO is further shown to confer pro-inflammatory gain of function activities as monitored by
NF-kappaB activation and surface
vascular cell adhesion molecule levels on aortic endothelial cells exposed to MPO-oxidized HDL. The loss of non-
cholesterol efflux activities and the gain of pro-inflammatory functions requires modification of the entire particle and can be recapitulated by oxidation of reconstituted HDL particles comprised of apoA1 and nonoxidizable
phosphatidylcholine species. Multiple site-directed mutagenesis studies of apoA1 suggest that the pro-inflammatory activity of MPO-modified HDL does not involve
methionine,
tyrosine, or
tryptophan,
oxidant-sensitive residues previously mapped as sites of apoA1 oxidation within human
atheroma. Thus, MPO-catalyzed oxidation of HDL results not only in the loss of classic atheroprotective reverse
cholesterol transport activities of the
lipoprotein but also both the loss of non-
cholesterol efflux related activities and the gain of pro-inflammatory functions.