title: Increased low-density lipoprotein oxidation and impaired high-density lipoprotein antioxidant defense are associated with increased macrophage homing and atherosclerosis in dyslipidemic obese mice: LCAT gene transfer decreases atherosclerosis.
abstract: BACKGROUND
  Obesity-associated dyslipidemia in humans is associated with increased low-density lipoprotein (LDL) oxidation. Mice with combined leptin and LDL receptor deficiency are obese and show severe dyslipidemia and insulin resistance. We investigated the association between oxidation of apolipoprotein B-containing lipoproteins, high-density lipoprotein (HDL) antioxidant defense, and atherosclerosis in these mice.
  
  
  RESULTS
  LDL receptor knockout (LDLR-/-), leptin-deficient (ob/ob), double-mutant (LDLR-/-;ob/ob), and C57BL6 mice were fed standard chow. Double-mutant mice had higher levels of non-HDL (P<0.001) and HDL (P<0.01) cholesterol and of triglycerides (P<0.001). They also had higher oxidative stress, evidenced by higher titers of autoantibodies against malondialdehyde-modified LDL (P<0.001). C57BL6 and ob/ob mice had no detectable lesions. Lesions covered 20% of total area of the thoracic abdominal aorta in double-mutant mice compared with 3.5% in LDLR-/- mice (P<0.01). Higher macrophage homing and accumulation of oxidized apolipoprotein B-100-containing lipoproteins were associated with larger plaque volumes in the aortic root of double-mutant mice (P<0.01). The activity of the HDL-associated antioxidant enzymes paraoxonase and lecithin:cholesterol acyltransferase (LCAT) (ANOVA; P<0.0001 for both) was lower in double-mutant mice. Adenovirus-mediated LCAT gene transfer in double-mutant mice increased plasma LCAT activity by 64% (P<0.01) and reduced the titer of autoantibodies by 40% (P<0.01) and plaque volume in the aortic root by 42% (P<0.05) at 6 weeks.
  
  
  CONCLUSIONS
  Dyslipidemia and insulin resistance in obese LDL receptor-deficient mice are associated with increased oxidative stress and impaired HDL-associated antioxidant defense, evidenced by decreased paraoxonase and LCAT activity. Transient LCAT overexpression was associated with a reduction of oxidative stress and atherosclerosis.
authors.affiliation: Cardiovascular Research Unit at the Center for Experimental Surgery and Anesthesiology, Katholieke Universiteit Leuven, Campus Gasthuisberg, O&N, Herestraat 49, B-3000 Leuven, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Mertens
authors.forename: Peter
authors.initials: P
authors.lastname: Verhamme
authors.forename: John K
authors.initials: JK
authors.lastname: Bielicki
authors.forename: Michael C
authors.initials: MC
authors.lastname: Phillips
authors.forename: Rozenn
authors.initials: R
authors.lastname: Quarck
authors.forename: Wim
authors.initials: W
authors.lastname: Verreth
authors.forename: Dominique
authors.initials: D
authors.lastname: Stengel
authors.forename: Ewa
authors.initials: E
authors.lastname: Ninio
authors.forename: Mohamad
authors.initials: M
authors.lastname: Navab
authors.forename: Bharti
authors.initials: B
authors.lastname: Mackness
authors.forename: Mike
authors.initials: M
authors.lastname: Mackness
authors.forename: Paul
authors.initials: P
authors.lastname: Holvoet
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001161:Arteriosclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D043303:Aryldialkylphosphatase; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002460:Cell Line; D002465:Cell Movement; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D004950:Esterases / Q000378:metabolism; D006949:Hyperlipidemias / Q000150:complications; D008055:Lipids / Q000097:blood; D008075:Lipoproteins, HDL / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics* / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics
chemical_list: D000975:Antioxidants; D015815:Cell Adhesion Molecules; D008055:Lipids; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; C099252:oxidized low density lipoprotein; D002784:Cholesterol; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D004950:Esterases; D043303:Aryldialkylphosphatase