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(American Journal of Pathology. 2006;169:303-313.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.050885

Reduced Acute Vascular Injury and Atherosclerosis in Hyperlipidemic Mice Transgenic for Lysozyme

Huixian Liu*, Feng Zheng*, Zhu Li*, Jaime Uribarri{dagger}, Bin Ren*, Randolph Hutter{ddagger}, James R. Tunstead{ddagger}, Juan Badimon{ddagger}, Gary E. Striker{dagger} and Helen Vlassara*

From The Brookdale Department of Geriatrics,* Division of Experimental Diabetes and Aging, the Cardiovascular Institute,{ddagger} the Division of Nephrology,{dagger} Department of Medicine, Mount Sinai School of Medicine, New York, New York

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.




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