[HTML][HTML] Apolipoprotein AI is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease

L Zheng, B Nukuna, ML Brennan… - The Journal of …, 2004 - Am Soc Clin Investig
L Zheng, B Nukuna, ML Brennan, M Sun, M Goormastic, M Settle, D Schmitt, X Fu…
The Journal of clinical investigation, 2004Am Soc Clin Investig
In recent studies we demonstrated that systemic levels of protein-bound nitrotyrosine
(NO2Tyr) 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 AI (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 …
In recent studies we demonstrated that systemic levels of protein-bound nitrotyrosine (NO2Tyr) 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 NO2Tyr 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 NO2Tyr and ClTyr contents of apoA-I are markedly higher in individuals with cardiovascular disease (CVD). Analysis of circulating HDL further reveals that higher NO2Tyr 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.
The Journal of Clinical Investigation