期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 32, 期 1, 页码 74-U190出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.111.238402
关键词
atherosclerosis; macrophages; metalloproteinases; inflammation; lipotoxicity
资金
- Telethon [GGP08065]
- Fondazione Roma
- Juvenile Diabetes Research Foundation [1-2007-665]
- Ministry of Health RF [7-Health-241913-FLORINASH]
Objective-Tissue inhibitor of metalloproteinase 3 (TIMP3) is a stromal protein that inhibits the activity of proteases and receptors. TIMP3 is downregulated in metabolic and inflammatory disorders, such as type 2 diabetes mellitus and atherosclerosis, particularly in regions enriched with monocyte/macrophage cells. To investigate the role of TIMP3 in atherosclerosis, we generated a new mouse model in which Timp3 was overexpressed in the atherosclerotic plaque via a macrophage-specific promoter (MacT3). We elucidated any potential antiatherosclerotic effects of TIMP3, including regulation of monocyte/macrophage recruitment within atherosclerotic plaques, in MacT3 mice crossbred with low-density lipoprotein receptor knockout (LDLR-/-) mice. Methods and Results-MacT3/LDLR-/- mice had an improvement of atherosclerosis and metabolic parameters compared with LDLR-/-. En face aorta and aortic root examination of MacT3/LDLR-/- mice revealed smaller atherosclerotic plaques with features of stability, such as increased collagen content and decreased necrotic core formation. Atherosclerotic plaques in MacT3/LDLR-/- mice contained fewer T cells and macrophages. Furthermore, TIMP3 overexpression in macrophages resulted in reduced oxidative stress signals, as evidenced by lower lipid peroxidation, protein carbonylation, and nitration in atheromas. Conclusion-Our study confirmed that macrophage-specific overexpression of TIMP3 decreases the inflammatory content and the amplitude of atherosclerotic plaques in mice. (Arterioscler Thromb Vasc Biol. 2012;32:74-81.)
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