Apolipoprotein A-I is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease.
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.
Department of Cell Biology, Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Lemin
L
Zheng
Benedicta
B
Nukuna
Marie-Luise
ML
Brennan
Mingjiang
M
Sun
Marlene
M
Goormastic
Megan
M
Settle
Dave
D
Schmitt
Xiaoming
X
Fu
Leonor
L
Thomson
Paul L
PL
Fox
Harry
H
Ischiropoulos
Jonathan D
JD
Smith
Michael
M
Kinter
Stanley L
SL
Hazen
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000368:Aged; D000818:Animals; D001011:Aorta / Q000737:chemistry / Q000473:pathology; D016632:Apolipoprotein A-I / Q000097:blood / Q000378:metabolism*; D001161:Arteriosclerosis / Q000503:physiopathology; D015153:Blotting, Western; D002318:Cardiovascular Diseases / Q000378:metabolism* / Q000503:physiopathology*; D002384:Catalysis; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D015331:Cohort Studies; D005260:Female; D005263:Femoral Artery / Q000737:chemistry / Q000473:pathology; D006801:Humans; D008075:Lipoproteins, HDL / Q000737:chemistry / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D009574:Nitro Compounds / Q000378:metabolism; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000097:blood / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D009574:Nitro Compounds; D014443:Tyrosine; D002784:Cholesterol; D009195:Peroxidase