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CKIP-1 limits foam cell formation and inhibits atherosclerosis by promoting degradation of Oct-1 by REGγ.

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.

SUBMITTER: Fan J

PROVIDER: S-EPMC6347643 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Vascular smooth muscle cells (VSMCs) are indispensable components in foam cell formation in atherosclerosis. However, the mechanism behind foam cell formation of VSMCs has not been addressed. We found a potential association between deletion of smooth muscle (SM) 22α and deregulated nuclear receptors liver X receptors (LXRs)/retinoid X receptor (RXR) signaling in mice. Here, we investigated the roles of SM22α in LXRα-modulated cholesterol homeostasis, and explore possible mechanisms underlying this process. We identified that the depletion of SM22α was a primary event driving VSMC cholesterol accumulation and the development of atherosclerosis in mice. Proteomic and lipidomic analysis validated that downregulation of SM22α was correlated with reduced expression of LXRα and ATP-binding cassette transporter (ABCA) 1 and increased cholesteryl ester in phenotypically modulated VSMCs induced by platelets-derived growth factor (PDGF)-BB. Notably, LXRα was mainly distributed in the cytoplasm rather than the nucleus in the neointimal and Sm22α-/- VSMCs. Loss of SM22α inhibited the nuclear import of LXRα and reduced ABCA1-mediated cholesterol efflux via promoting depolymerization of actin stress fibers. Affinity purification and mass spectrometry (AP-MS) analysis, co-immunoprecipitation and GST pull-down assays, confocal microscopy, and stochastic optical reconstruction microscopy (STORM) revealed that globular-actin (G-actin), monomeric actin, interacted with and retained LXRα in the cytoplasm in PDGF-BB-treated and Sm22α-/- VSMCs. This interaction blocked LXRα binding to Importin α, a karyopherin that mediates the trafficking of macromolecules across the nuclear envelope, and the resulting reduction of LXRα transcriptional activity. Increasing SM22α expression restored nuclear localization of LXRα and removed cholesterol accumulation via inducing actin polymerization, ameliorating atherosclerosis. Our findings highlight that LXRα is a mechanosensitive nuclear receptor and that the nuclear import of LXRα maintained by the SM22α-actin axis is a potential target for blockade of VSMC foam cell formation and development of anti-atherosclerosis.

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CKIP-1 limits foam cell formation and inhibits atherosclerosis by promoting degradation of Oct-1 by REGγ.

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