title: Effects of native and myeloperoxidase-modified apolipoprotein a-I on reverse cholesterol transport and atherosclerosis in mice.
abstract: OBJECTIVE
  Preclinical and clinical studies have shown beneficial effects of infusions of apolipoprotein A-I (ApoA-I) on atherosclerosis. ApoA-I is also a target for myeloperoxidase-mediated oxidation, leading in vitro to a loss of its ability to promote ATP-binding cassette transporter A1-dependent macrophage cholesterol efflux. Therefore, we hypothesized that myeloperoxidase-mediated ApoA-I oxidation would impair its promotion of reverse cholesterol transport in vivo and the beneficial effects on atherosclerotic plaques.
  
  
  RESULTS
  ApoA-I(-/-) or apolipoprotein E-deficient mice were subcutaneously injected with native human ApoA-I, oxidized human ApoA-I (myeloperoxidase/hydrogen peroxide/chloride treated), or carrier. Although early postinjection (8 hours) levels of total ApoA-I in plasma were similar for native versus oxidized human ApoA-I, native ApoA-I primarily resided within the high-density lipoprotein fraction, whereas the majority of oxidized human ApoA-I was highly cross-linked and not high-density lipoprotein particle associated, consistent with impaired ATP-binding cassette transporter A1 interaction. In ApoA-I(-/-) mice, ApoA-I oxidation significantly impaired reverse cholesterol transport in vivo. In advanced aortic root atherosclerotic plaques of apolipoprotein E-deficient mice, native ApoA-I injections led to significant decreases in lipid content, macrophage number, and an increase in collagen content; in contrast, oxidized human ApoA-I failed to mediate these changes. The decrease in plaque macrophages with native ApoA-I was accompanied by significant induction of their chemokine receptor CCR7. Furthermore, only native ApoA-I injections led to a significant reduction of inflammatory M1 and increase in anti-inflammatory M2 macrophage markers in the plaques.
  
  
  CONCLUSIONS
  Myeloperoxidase-mediated oxidation renders ApoA-I dysfunctional and unable to (1) promote reverse cholesterol transport, (2) mediate beneficial changes in the composition of atherosclerotic plaques, and (3) pacify the inflammatory status of plaque macrophages.
authors.affiliation: From the Department of Medicine, Division of Cardiology and the Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine (B.H., S.P., T.B., W.K.K.C., Y.M.A., T.H., B.R., E.A.F.); Medizinische Klinik für Kardiologie und Angiologie, Charité-Universitaetsmedizin Berlin, Berlin, Germany (B.H.); and Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, OH (T.C.T., M.S.S.Y., J.A.D., Y.H., J.B., S.Z.B., J.D.S., S.L.H.).
authors.forename: Bernd
authors.initials: B
authors.lastname: Hewing
authors.forename: Saj
authors.initials: S
authors.lastname: Parathath
authors.forename: Tessa
authors.initials: T
authors.lastname: Barrett
authors.forename: Wing Ki Kellie
authors.initials: WK
authors.lastname: Chung
authors.forename: Yaritzy M
authors.initials: YM
authors.lastname: Astudillo
authors.forename: Tadateru
authors.initials: T
authors.lastname: Hamada
authors.forename: Bhama
authors.initials: B
authors.lastname: Ramkhelawon
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Tallant
authors.forename: Mohamed Shaif S
authors.initials: MS
authors.lastname: Yusufishaq
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Didonato
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Buffa
authors.forename: Stela Z
authors.initials: SZ
authors.lastname: Berisha
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Smith
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D016632:Apolipoprotein A-I / Q000008:administration & dosage / Q000097:blood* / Q000172:deficiency / Q000235:genetics; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D001692:Biological Transport; D002460:Cell Line; D002784:Cholesterol / Q000097:blood*; D008076:Cholesterol, HDL / Q000097:blood; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D007279:Injections, Subcutaneous; D008264:Macrophages / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000378:metabolism*; D058226:Plaque, Atherosclerotic; D054400:Receptors, CCR7 / Q000378:metabolism
chemical_list: D064286:ATP Binding Cassette Transporter 1; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D002784:Cholesterol; D008076:Cholesterol, HDL; D003094:Collagen; D009195:Peroxidase; D054400:Receptors, CCR7; C577833:Abca1 protein, mouse; C505693:APOA1 protein, human; C515371:Ccr7 protein, mouse
keywords: apolipoprotein A-I; atherosclerosis; myeloperoxidase