title: Reduced acute vascular injury and atherosclerosis in hyperlipidemic mice transgenic for lysozyme.
abstract: Hyperlipidemia promotes oxidant stress, inflammation, and atherogenesis in apolipoprotein E-deficient (ApoE((-/-))) mice. Mice transgenic for lysozyme (LZ-Tg) are resistant to acute and chronic oxidative stress and have decreased circulating levels of pro-oxidant advanced glycation end-products (AGEs). Herein we report that TIB-186 macrophages transduced with adenovirus-expressing human LZ (AdV-LZ) containing the AGE-binding domain facilitated AGE uptake and degradation and that AdV-LZ-transduced macrophages and peritoneal macrophages from LZ-Tg mice suppressed the AGE-triggered tumor necrosis factor-alpha response. We assessed atherosclerosis in LZ-Tg mice crossed with ApoE((-/-)) mice (LZ/ApoE((-/-))) and found increased serum LZ levels and decreased AGE and 8-isoprostanes levels, although hyperlipidemia remained similar to ApoE((-/-)) controls. Atherosclerotic plaques and neointimal lesions at the aortic root and descending aorta were markedly decreased (by 40% and 80%, respectively) in LZ/ApoE((-/-)) versus ApoE((-/-)) mice, as were inflammatory infiltrates. The arterial lesions following femoral artery injury in LZ/ApoE((-/-)) mice were suppressed (intimal to media ratio decreased by 50%), as were AGE deposits and vascular smooth muscle cell activation, compared to ApoE((-/-)) mice. Despite hyperlipidemia, development of atheroma and occlusive, inflammatory arterial neointimal lesions in response to injury was suppressed in LZ/ApoE((-/-)) mice. This effect may be due to the antioxidant properties of LZ, which is possibly linked to the AGE-binding domain region of the molecule.
authors.affiliation: The Brookdale Department of Geriatrics, Division of Experimental Diabetes and Aging, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Huixian
authors.initials: H
authors.lastname: Liu
authors.forename: Feng
authors.initials: F
authors.lastname: Zheng
authors.forename: Zhu
authors.initials: Z
authors.lastname: Li
authors.forename: Jaime
authors.initials: J
authors.lastname: Uribarri
authors.forename: Bin
authors.initials: B
authors.lastname: Ren
authors.forename: Randolph
authors.initials: R
authors.lastname: Hutter
authors.forename: James R
authors.initials: JR
authors.lastname: Tunstead
authors.forename: Juan
authors.initials: J
authors.lastname: Badimon
authors.forename: Gary E
authors.initials: GE
authors.lastname: Striker
authors.forename: Helen
authors.initials: H
authors.lastname: Vlassara
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D002478:Cells, Cultured; D005263:Femoral Artery / Q000293:injuries / Q000473:pathology; D005822:Genetic Vectors; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D006949:Hyperlipidemias / Q000150:complications*; D007150:Immunohistochemistry; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009113:Muramidase / Q000235:genetics* / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D011994:Recombinant Proteins; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D017127:Glycation End Products, Advanced; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D009113:Muramidase