Overexpression of Tissue Inhibitor of Metalloproteinase 3 in Macrophages Reduces Atherosclerosis in Low-Density Lipoprotein Receptor Knockout Mice
Overexpression of Tissue Inhibitor of Metalloproteinase 3 in Macrophages Reduces Atherosclerosis in Low-Density Lipoprotein Receptor Knockout Mice
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DOI：
10.1161/atvbaha.111.238402
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发表时间：
2012-01-01
影响因子：
8.7
通讯作者：
Federici, Massimo
中科院分区：
文献类型：
--
作者：
Casagrande, Viviana;Menghini, Rossella;Federici, Massimo
金属蛋白酶组织抑制剂3（TIMP 3）是一种基质蛋白，抑制蛋白酶和受体的活性。TIMP 3在代谢和炎性疾病如2型糖尿病和动脉粥样硬化中下调，特别是在富含单核细胞/巨噬细胞的区域。为了研究TIMP 3在动脉粥样硬化中的作用，我们建立了一种新的小鼠模型，其中TIMP 3通过巨噬细胞特异性启动子（MacT 3）在动脉粥样硬化斑块中过表达。我们阐明了任何潜在的抗动脉粥样硬化作用的TIMP 3，包括调节单核细胞/巨噬细胞招募动脉粥样硬化斑块内，在MacT 3小鼠杂交与低密度脂蛋白受体敲除（LDLR-/-）mouse.Methods和Results-MacT 3/LDLR-/-mouse有改善动脉粥样硬化和代谢参数相比，LDLR-/-。MacT 3/LDLR-/-小鼠的主动脉和主动脉根部检查显示动脉粥样硬化斑块较小，具有稳定性特征，如胶原含量增加和坏死核心形成减少。MacT 3/LDLR-/-小鼠中的动脉粥样硬化斑块含有较少的T细胞和巨噬细胞。此外，TIMP 3在巨噬细胞中的过度表达导致氧化应激信号减少，证明了较低的脂质过氧化，蛋白质羰基化，和硝化在atheroams. Conclusion，我们的研究证实，巨噬细胞特异性过度表达TIMP 3减少炎症内容和振幅的小鼠动脉粥样硬化斑块。（Arterioscler Thromb Vasc Biol.2012;32：74-81.）
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.)