title: Human apolipoprotein A-II enrichment displaces paraoxonase from HDL and impairs its antioxidant properties: a new mechanism linking HDL protein composition and antiatherogenic potential.
abstract: Apolipoprotein A-II (apoA-II), the second major high-density lipoprotein (HDL) apolipoprotein, has been linked to familial combined hyperlipidemia. Human apoA-II transgenic mice constitute an animal model for this proatherogenic disease. We studied the ability of human apoA-II transgenic mice HDL to protect against oxidative modification of apoB-containing lipoproteins. When challenged with an atherogenic diet, antigens related to low-density lipoprotein (LDL) oxidation were markedly increased in the aorta of 11.1 transgenic mice (high human apoA-II expressor). HDL from control mice and 11.1 transgenic mice were coincubated with autologous very LDL (VLDL) or LDL, or with human LDL under oxidative conditions. The degree of oxidative modification of apoB lipoproteins was then evaluated by measuring relative electrophoretic mobility, dichlorofluorescein fluorescence, 9- and 13-hydroxyoctadecadienoic acid content, and conjugated diene kinetics. In all these different approaches, and in contrast to control mice, HDL from 11.1 transgenic mice failed to protect LDL from oxidative modification. A decreased content of apoA-I, paraoxonase (PON1), and platelet-activated factor acetyl-hydrolase activities was found in HDL of 11.1 transgenic mice. Liver gene expression of these HDL-associated proteins did not differ from that of control mice. In contrast, incubation of isolated human apoA-II with control mouse plasma at 37 degrees C decreased PON1 activity and displaced the enzyme from HDL. Thus, overexpression of human apoA-II in mice impairs the ability of HDL to protect apoB-containing lipoproteins from oxidation. Further, the displacement of PON1 by apoA-II could explain in part why PON1 is mostly found in HDL particles with apoA-I and without apoA-II, as well as the poor antiatherogenic properties of apoA-II-rich HDL.
authors.affiliation: Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Vicent
authors.initials: V
authors.lastname: Ribas
authors.forename: José Luis
authors.initials: JL
authors.lastname: Sánchez-Quesada
authors.forename: Rosa
authors.initials: R
authors.lastname: Antón
authors.forename: Mercedes
authors.initials: M
authors.lastname: Camacho
authors.forename: Josep
authors.initials: J
authors.lastname: Julve
authors.forename: Joan Carles
authors.initials: JC
authors.lastname: Escolà-Gil
authors.forename: Luís
authors.initials: L
authors.lastname: Vila
authors.forename: Jordi
authors.initials: J
authors.lastname: Ordóñez-Llanos
authors.forename: Francisco
authors.initials: F
authors.lastname: Blanco-Vaca
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001018:Aortic Diseases / Q000209:etiology / Q000378:metabolism; D016632:Apolipoprotein A-I / Q000378:metabolism; D016633:Apolipoprotein A-II / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D001161:Arteriosclerosis / Q000209:etiology / Q000378:metabolism; D043303:Aryldialkylphosphatase / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000097:blood; D004036:Diet, Atherogenic; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000097:blood / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000502:physiology; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis
chemical_list: D016632:Apolipoprotein A-I; D016633:Apolipoprotein A-II; D008076:Cholesterol, HDL; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D011993:Recombinant Fusion Proteins; D017392:Thiobarbituric Acid Reactive Substances; C099252:oxidized low density lipoprotein; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D043303:Aryldialkylphosphatase