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Abstract
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 REGγ 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.
Highlights
The PH domain-containing protein CKIP-1 was originally identified as an interacting protein of CK2 kinase and was further shown to play a crucial role in the regulation of tumorigenesis, cell apoptosis, cell morphology, and the actin cytoskeleton[4,5,6,7,8]
We found that only oxidized LDL (oxLDL), but not unmodified LDL or acetylated LDL, upregulated CKIP-1 expression on bone marrowderived macrophages (BMDMs) (Fig. 1c)
To explore the role of CKIP-1 in the foam cell formation, wild-type (WT) and Ckip-1−/− BMDMs were incubated with oxLDL or serum from atherosclerosis-prone apolipoprotein E-deficient (Apoe−/−) mice, which contained atherogenic lipoprotein to induce foam cell formation
Summary
The PH (pleckstrin homology) domain-containing protein CKIP-1 ( known as PLEKHO1) was originally identified as an interacting protein of CK2 kinase and was further shown to play a crucial role in the regulation of tumorigenesis, cell apoptosis, cell morphology, and the actin cytoskeleton[4,5,6,7,8]. Since macrophage plays a critical role in the development of atherosclerosis[12,13], we hypothesized that CKIP-1 might participate in the regulation of atherogenesis. Bone marrow transplantation reveals that Ckip-1 deficiency in hematopoietic cells is sufficient to increase atherosclerotic plaque formation. These findings provide insights to the role of CKIP-1 in the pathogenesis of atherosclerosis
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