title: MCP-1 binds to oxidized LDL and is carried by lipoprotein(a) in human plasma.
abstract: Lipoprotein oxidation plays an important role in pathogenesis of atherosclerosis. Oxidized low density lipoprotein (OxLDL) induces profound inflammatory responses in vascular cells, such as production of monocyte chemoattractant protein-1 (MCP-1) [chemokine (C-C motif) ligand 2], a key chemokine in the initiation and progression of vascular inflammation. Here we demonstrate that OxLDL also binds MCP-1 and that the OxLDL-bound MCP-1 retains its ability to recruit monocytes. A human MCP-1 mutant in which basic amino acids Arg-18 and Lys-19 were replaced with Ala did not bind to OxLDL. The MCP-1 binding to OxLDL was inhibited by the monoclonal antibody E06, which binds oxidized phospholipids (OxPLs) in OxLDL. Because OxPLs are carried by lipoprotein(a) [Lp(a)] in human plasma, we tested to determine whether Lp(a) binds MCP-1. Recombinant wild-type but not mutant MCP-1 added to human plasma bound to Lp(a), and its binding was inhibited by E06. Lp(a) captured from human plasma contained MCP-1 and the Lp(a)-associated endogenous MCP-1 induced monocyte migration. These results demonstrate that OxLDL and Lp(a) bind MCP-1 in vitro and in vivo and that OxPLs are major determinants of the MCP-1 binding. The association of MCP-1 with OxLDL and Lp(a) may play a role in modulating monocyte trafficking during atherogenesis.
authors.affiliation: Department of Medicine, University of California, San Diego, San Diego, CA, USA.
authors.forename: Philipp
authors.initials: P
authors.lastname: Wiesner
authors.forename: Maria
authors.initials: M
authors.lastname: Tafelmeier
authors.forename: Dominik
authors.initials: D
authors.lastname: Chittka
authors.forename: Soo-Ho
authors.initials: SH
authors.lastname: Choi
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Young Sup
authors.initials: YS
authors.lastname: Byun
authors.forename: Felicidad
authors.initials: F
authors.lastname: Almazan
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Yang
authors.forename: Navaid
authors.initials: N
authors.lastname: Iqbal
authors.forename: Punam
authors.initials: P
authors.lastname: Chowdhury
authors.forename: Alan
authors.initials: A
authors.lastname: Maisel
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Witztum
authors.forename: Tracy M
authors.initials: TM
authors.lastname: Handel
authors.forename: Sotirios
authors.initials: S
authors.lastname: Tsimikas
authors.forename: Yury I
authors.initials: YI
authors.lastname: Miller
mesh_terms: D000818:Animals; D001665:Binding Sites; D018932:Chemokine CCL2 / Q000097:blood / Q000378:metabolism*; D006801:Humans; D017270:Lipoprotein(a) / Q000097:blood* / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000097:blood / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011994:Recombinant Proteins / Q000097:blood / Q000378:metabolism
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D017270:Lipoprotein(a); D008077:Lipoproteins, LDL; D011994:Recombinant Proteins; C099252:oxidized low density lipoprotein
keywords: chemokine (C-C motif) ligand 2; monocyte chemoattractant protein-1; monocyte migration; oxidized low density lipoprotein