CKIP-1 limits foam cell formation and inhibits atherosclerosis by promoting degradation of Oct-1 by REGγ
CKIP-1 limits foam cell formation and inhibits atherosclerosis by promoting degradation of Oct-1 by REGγ
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CKIP-1 通过促进 REGγ 降解 Oct-1 来限制泡沫细胞形成并抑制动脉粥样硬化
DOI：
10.1038/s41467-018-07895-3
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发表时间：
2019-01-25
影响因子：
16.6
通讯作者：
Zhang, Lingqiang
中科院分区：
文献类型：
--
作者：
Fan, Jiao;Liu, Lifeng;Zhang, Lingqiang
动脉粥样硬化相关的心血管疾病是全球死亡的主要原因。巨噬细胞摄取修饰的脂蛋白并转化为泡沫细胞，引发炎症反应，从而促进斑块形成。在这里，我们表明，酪蛋白激酶2相互作用蛋白-1（CKIP-1）是泡沫细胞形成和动脉粥样硬化的抑制剂。Ckip-1缺乏导致小鼠脂蛋白摄取增加和泡沫细胞形成，表明CKIP-1在此过程中具有保护作用。Ckip-1的消融特异性上调清道夫受体LOX-1的转录，但不上调CD 36和SR-A的转录。在机制上，CKIP-1与蛋白酶体激活剂REG γ相互作用，并靶向转录因子Oct-1进行降解，从而通过Oct-1抑制LOX-1的转录。此外，Ckip-1缺陷小鼠经历加速的动脉粥样硬化，骨髓移植揭示造血细胞中的Ckip-1缺陷足以增加动脉粥样硬化斑块的形成。因此，CKIP-1通过调节泡沫细胞形成和胆固醇代谢发挥重要的抗动脉粥样硬化作用。
Atherosclerosis-related cardiovascular diseases are the leading cause of mortality worldwide. Macrophages uptake modified lipoproteins and transform into foam cells, triggering an inflammatory response and thereby promoting plaque formation. Here we show that casein kinase 2-interacting protein-1 (CKIP-1) is a suppressor of foam cell formation and atherosclerosis. Ckip-1 deficiency in mice leads to increased lipoprotein uptake and foam cell formation, indicating a protective role of CKIP-1 in this process. Ablation of Ckip-1 specifically upregulates the transcription of scavenger receptor LOX-1, but not that of CD36 and SR-A. Mechanistically, CKIP-1 interacts with the proteasome activator REG gamma and targets the transcriptional factor Oct-1 for degradation, thereby suppressing the transcription of LOX-1 by Oct-1. Moreover, Ckip-1-deficient mice undergo accelerated atherosclerosis, and bone marrow transplantation reveals that Ckip-1 deficiency in hematopoietic cells is sufficient to increase atherosclerotic plaque formation. Therefore, CKIP-1 plays an essential anti-atherosclerotic role through regulation of foam cell formation and cholesterol metabolism.