title: Arg123-Tyr166 domain of human ApoA-I is critical for HDL-mediated inhibition of macrophage homing and early atherosclerosis in mice.
abstract: Atherosclerosis was studied in apolipoprotein E (apoE) knockout mice expressing human apolipoprotein A-I (apoA-I) or an apoA-I/apolipoprotein A-II (apoA-II) chimera in which the Arg123-Tyr166 central domain of apoA-I was substituted with the Ser12-Ala75 segment of apoA-II. High density lipoprotein (HDL) cholesterol levels were identical in apoA-I and apoA-I/apoA-II mice, but at 4 months, plaques were 2.7-fold larger in the aortic root of the apoA-I/apoA-II mice (P<0.01). The macrophage-to-smooth muscle cell ratio of lesions was 2.1-fold higher in apo-I/apoA-II mice than in apoA-I mice (P<0.01). This was due to a 2.7-fold higher (P<0.001) in vivo macrophage homing in the aortic root of apoA-I/apoA-II mice. Plasma platelet-activating factor acetyl hydrolase activity was lower (P<0.01) in apoA-I/apoA-II mice, resulting in increased oxidative stress, as evidenced by the higher titer of antibodies against oxidized low density lipoprotein (P<0.01). Increased oxidative stress resulted in increased stimulation of ex vivo macrophage adhesion by apoA-I/apoA-II beta-very low density lipoprotein and decreased inhibition of beta-very low density lipoprotein-induced adhesion by HDL from apoA-I/apoA-II mice. The cellular cholesterol efflux capacity of HDL from apoA-I/apoA-II mice was very similar to that of apoA-I mice. Thus, the Arg123-Tyr166 central domain of apoA-I is critical for reducing oxidative stress, macrophage homing, and early atherosclerosis in apoE knockout mice independent of its role in HDL production and cholesterol efflux.
authors.affiliation: Center for Experimental Surgery and Anesthesiology, Katholieke Universiteit Leuven, Leuven, Belgium. paul.holvoet@med.kuleuven.ac.be
authors.forename: P
authors.initials: P
authors.lastname: Holvoet
authors.forename: K
authors.initials: K
authors.lastname: Peeters
authors.forename: S
authors.initials: S
authors.lastname: Lund-Katz
authors.forename: A
authors.initials: A
authors.lastname: Mertens
authors.forename: P
authors.initials: P
authors.lastname: Verhamme
authors.forename: R
authors.initials: R
authors.lastname: Quarck
authors.forename: D
authors.initials: D
authors.lastname: Stengel
authors.forename: M
authors.initials: M
authors.lastname: Lox
authors.forename: E
authors.initials: E
authors.lastname: Deridder
authors.forename: H
authors.initials: H
authors.lastname: Bernar
authors.forename: M
authors.initials: M
authors.lastname: Nickel
authors.forename: G
authors.initials: G
authors.lastname: Theilmeier
authors.forename: E
authors.initials: E
authors.lastname: Ninio
authors.forename: M C
authors.initials: MC
authors.lastname: Phillips
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics*; D001161:Arteriosclerosis / Q000503:physiopathology*; D001323:Autoantibodies / Q000032:analysis; D001483:Base Sequence; D002448:Cell Adhesion; D002678:Chimera; D008076:Cholesterol, HDL / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D008075:Lipoproteins, HDL / Q000097:blood; D008077:Lipoproteins, LDL / Q000276:immunology; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000235:genetics
chemical_list: D016632:Apolipoprotein A-I; D001323:Autoantibodies; D008076:Cholesterol, HDL; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL