In recent studies we demonstrated that systemic levels of
protein-bound
nitrotyrosine (
NO(2)Tyr) and
myeloperoxidase (MPO), a
protein that catalyzes generation of nitrating
oxidants, serve as independent predictors of atherosclerotic risk, burden, and incident
cardiac events. We now show both that
apolipoprotein A-I (
apoA-I), the primary
protein constituent of HDL, is a selective target for MPO-catalyzed nitration and chlorination in vivo and that MPO-catalyzed oxidation of HDL and
apoA-I results in selective inhibition in ABCA1-dependent
cholesterol efflux from macrophages. Dramatic selective enrichment in
NO(2)Tyr and chlorotyrosine (ClTyr) content within
apoA-I recovered from serum and human atherosclerotic lesions is noted, and analysis of serum from sequential subjects demonstrates that the
NO(2)Tyr and ClTyr contents of
apoA-I are markedly higher in individuals with
cardiovascular disease (CVD). Analysis of circulating HDL further reveals that higher
NO(2)Tyr and ClTyr contents of the
lipoprotein are each significantly associated with diminished ABCA1-dependent
cholesterol efflux capacity of the
lipoprotein. MPO as a likely mechanism for oxidative modification of
apoA-I in vivo is apparently facilitated by MPO binding to
apoA-I, as revealed by cross-immunoprecipitation studies in plasma, recovery of MPO within HDL-like particles isolated from human
atheroma, and identification of a probable contact site between the
apoA-I moiety of HDL and MPO. To our knowledge, the present results provide the first direct evidence for
apoA-I as a selective target for MPO-catalyzed oxidative modification in human
atheroma. They also suggest a potential mechanism for MPO-dependent generation of a proatherogenic dysfunctional form of HDL in vivo.