Inhibition of local macrophage growth ameliorates focal inflammation and suppresses atherosclerosis.
Inhibition of local macrophage growth ameliorates focal inflammation and suppresses atherosclerosis.
复制标题
抑制局部巨噬细胞生长可改善局部炎症并抑制动脉粥样硬化。
DOI：
10.1161/atvbaha.117.310320
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Araki E
中科院分区：
文献类型：
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作者：
Yamada S;Senokuchi T;Matsumura T;Morita Y;Ishii N;Fukuda K;Murakami S;Nishida S;Kawasaki S;Motoshima H;Furukawa N;Komohara Y;Fujiwara Y;Koga T;Yamagata K;Takeya M;Araki E
目的巨噬细胞在动脉粥样硬化斑块形成和发展的不同阶段发挥核心作用。据报道，局部巨噬细胞在动脉粥样硬化期间增殖，但巨噬细胞增殖在这方面的病理生理学意义尚不清楚。方法和结果在清道夫受体启动子/增强子的调控下，通过诱导细胞周期蛋白依赖的激酶抑制因子1B(也称为p27kip)的表达来抑制巨噬细胞的增殖。随后将巨噬细胞特异性的人p27kipTg小鼠与载脂蛋白E缺陷小鼠杂交，进行动脉粥样硬化斑块研究。结果表明，局部巨噬细胞数量的减少导致动脉粥样硬化斑块的形成和斑块内的炎症反应明显受到抑制。此外，在巨噬细胞特异性的人p27kipTg小鼠中，局部巨噬细胞的减少有助于斑块的稳定，表现为坏死核心面积减少，胶原细胞外基质增加，纤维帽增厚。结论这些结果为局部巨噬细胞增殖参与动脉粥样硬化斑块的形成、发展和斑块稳定性提供了直接证据。因此，控制巨噬细胞的增殖可能是治疗动脉粥样硬化性疾病的一个靶点。
ObjectiveMacrophages play a central role in various stages of atherosclerotic plaque formation and progression. The local macrophages reportedly proliferate during atherosclerosis, but the pathophysiological significance of macrophage proliferation in this context remains unclear. Here, we investigated the involvement of local macrophage proliferation during atherosclerosis formation and progression using transgenic mice, in which macrophage proliferation was specifically suppressed.Approach and ResultsInhibition of macrophage proliferation was achieved by inducing the expression of cyclin-dependent kinase inhibitor 1B, also known as p27kip, under the regulation of a scavenger receptor promoter/enhancer. The macrophage-specific human p27kipTg mice were subsequently crossed with apolipoprotein E–deficient mice for the atherosclerotic plaque study. Results showed that a reduced number of local macrophages resulted in marked suppression of atherosclerotic plaque formation and inflammatory response in the plaque. Moreover, fewer local macrophages in macrophage-specific human p27kipTg mice helped stabilize the plaque, as evidenced by a reduced necrotic core area, increased collagenous extracellular matrix, and thickened fibrous cap.ConclusionsThese results provide direct evidence of the involvement of local macrophage proliferation in formation and progression of atherosclerotic plaques and plaque stability. Thus, control of macrophage proliferation might represent a therapeutic target for treating atherosclerotic diseases.