Role of macrophage colony-stimulating factor in atherosclerosis: studies of osteopetrotic mice.
Role of macrophage colony-stimulating factor in atherosclerosis: studies of osteopetrotic mice.
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发表时间：
1997-05
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通讯作者：
J. Qiao;Jagannath Tripathi;N. Mishra;Y. Cai;S. Tripathi;X. Wang;S. Imes;Michael C Fishbein;Steven K. Clinton;Peter Libby;A. Lusis;T. Rajavashisth
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作者：
J. Qiao;Jagannath Tripathi;N. Mishra;Y. Cai;S. Tripathi;X. Wang;S. Imes;Michael C Fishbein;Steven K. Clinton;Peter Libby;A. Lusis;T. Rajavashisth
先前的体外和体内研究表明，巨噬细胞集落刺激因子（M-CSF）在动脉粥样硬化形成中起作用。为了验证这一假设，我们研究了骨硬化（OP/OP）小鼠的动脉粥样硬化形成，由于结构基因突变而缺乏M-CSF。通过给小鼠喂食高脂肪、高胆固醇饮食或将op小鼠与载脂蛋白E（apo E）敲除小鼠杂交以产生缺乏M-CSF和apo E的小鼠来诱导动脉粥样硬化形成。在饮食和载脂蛋白E基因敲除模型中，M-CSF缺乏导致动脉粥样硬化形成显著减少。例如，在载脂蛋白E基因敲除模型中，op突变的纯合性完全消除了雄性小鼠的主动脉粥样硬化形成，并使雌性小鼠的病变大小减少了约97%。op突变的杂合子小鼠也表现出病变大小的显著减小。在apo E基因敲除小鼠中，主动脉弓中动脉粥样硬化的频率为0/6（op/op）、1/15（op/+）和12/16（+/+）。M-CSF对动脉粥样硬化的影响似乎不是由血浆脂蛋白的变化介导的，因为op小鼠表现出更高水平的致动脉粥样硬化脂蛋白颗粒。op突变对动脉粥样硬化形成的影响可能是由于循环单核细胞减少、组织巨噬细胞减少或动脉M-CSF减少。
Previous in vitro and in vivo studies have suggested that macrophage colony-stimulating factor (M-CSF) plays a role in atherogenesis. To examine this hypothesis, we have studied atherogenesis in osteopetrotic (op/op) mice, which lack M-CSF due to a structural gene mutation. Atherogenesis was induced either by feeding the mice a high fat, high cholesterol diet or by crossing op mice with apolipoprotein E (apo E) knockout mice to generate mice lacking both M-CSF and apo E. In both the dietary and apo E knockout models, M-CSF deficiency resulted in significantly reduced atherogenesis. For example, in the apo E knockout model, homozygosity for the op mutation totally abolished aortic atherogenesis in male mice and reduced the size of the lesions approximately 97% in female mice. Mice heterozygous for the op mutation also exhibited a significant decrease in lesion size. Among apo E knockout mice, the frequency of atherosclerosis in aortic arch was 0/6 (op/op), 1/15 (op/+), and 12/16 (+/+). The effect of the M-CSF on atherosclerosis did not appear to be mediated by changes in plasma lipoproteins, as the op mice exhibited higher levels of atherogenic lipoprotein particles. The effects of the op mutation on atherogenesis may have resulted from decreased circulating monocytes, reduced tissue macrophages, or diminished arterial M-CSF.