title: Combined serum paraoxonase knockout/apolipoprotein E knockout mice exhibit increased lipoprotein oxidation and atherosclerosis.
abstract: Serum paraoxonase (PON1), present on high density lipoprotein, may inhibit low density lipoprotein (LDL) oxidation and protect against atherosclerosis. We generated combined PON1 knockout (KO)/apolipoprotein E (apoE) KO and apoE KO control mice to compare atherogenesis and lipoprotein oxidation. Early lesions were examined in 3-month-old mice fed a chow diet, and advanced lesions were examined in 6-month-old mice fed a high fat diet. In both cases, the PON1 KO/apoE KO mice exhibited significantly more atherosclerosis (50-71% increase) than controls. We examined LDL oxidation and clearance in vivo by injecting human LDL into the mice and following its turnover. LDL clearance was faster in the double KO mice as compared with controls. There was a greater rate of accumulation of oxidized phospholipid epitopes and a greater accumulation of LDL-immunoglobulin complexes in the double KO mice than in controls. Furthermore, the amounts of three bioactive oxidized phospholipids were elevated in the endogenous intermediate density lipoprotein/LDL of double KO mice as compared with the controls. Finally, the expression of heme oxygenase-1, peroxisome proliferator-activated receptor gamma, and oxidized LDL receptors were elevated in the livers of double KO mice as compared with the controls. These data demonstrate that PON1 deficiency promotes LDL oxidation and atherogenesis in apoE KO mice.
authors.affiliation: Division of Cardiology, Department of Medicine, UCLA, Los Angeles, California 90095, USA. dshih@mednet.ucla.edu
authors.forename: D M
authors.initials: DM
authors.lastname: Shih
authors.forename: Y R
authors.initials: YR
authors.lastname: Xia
authors.forename: X P
authors.initials: XP
authors.lastname: Wang
authors.forename: E
authors.initials: E
authors.lastname: Miller
authors.forename: L W
authors.initials: LW
authors.lastname: Castellani
authors.forename: G
authors.initials: G
authors.lastname: Subbanagounder
authors.forename: H
authors.initials: H
authors.lastname: Cheroutre
authors.forename: K F
authors.initials: KF
authors.lastname: Faull
authors.forename: J A
authors.initials: JA
authors.lastname: Berliner
authors.forename: J L
authors.initials: JL
authors.lastname: Witztum
authors.forename: A J
authors.initials: AJ
authors.lastname: Lusis
mesh_terms: D000818:Animals; D001021:Aortic Valve / Q000473:pathology; D001057:Apolipoproteins E / Q000097:blood* / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D043303:Aryldialkylphosphatase; D001323:Autoantibodies / Q000097:blood; D003433:Crosses, Genetic; D004036:Diet, Atherogenic; D004041:Dietary Fats; D004950:Esterases / Q000097:blood* / Q000172:deficiency / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D008077:Lipoproteins, LDL / Q000276:immunology / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout
chemical_list: D001057:Apolipoproteins E; D001323:Autoantibodies; D004041:Dietary Fats; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D004950:Esterases; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human