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

Fan, Junfen; Liu, Lifeng; Liu, Qing‐Yan; Cui, Yu; Yao, Binwei; Zhang, Minghua; Gao, Yabing; Fu, Yesheng; Dai, Hongmiao; Pan, Jing; Qiu, Ya; Liu, Cui Hua; He, Fuchu; Wang, Yu; Zhang, Lingqiang

doi:10.1038/s41467-018-07895-3

Cited by 49 publications

(28 citation statements)

References 37 publications

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“…Atherosclerosis is a chronic inflammatory disease and the formation of foam cells plays a key role in disease development 32,33 . Therefore, LPS-induced inflammation in macrophage and oxLDL-treated macrophage (foam cells formation) were selected as in vitro models for evaluating the therapeutic efficacy of MM-AT-NPs.…”

Section: Attenuation Effects Of Mm-at-nps On Inflammation In Vitromentioning

confidence: 99%

Treatment of atherosclerosis by macrophage-biomimetic nanoparticles via targeted pharmacotherapy and sequestration of proinflammatory cytokines

et al. 2020

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Vascular disease remains the leading cause of death and disability, the etiology of which often involves atherosclerosis. The current treatment of atherosclerosis by pharmacotherapy has limited therapeutic efficacy. Here we report a biomimetic drug delivery system derived from macrophage membrane coated ROS-responsive nanoparticles (NPs). The macrophage membrane not only avoids the clearance of NPs from the reticuloendothelial system, but also leads NPs to the inflammatory tissues, where the ROS-responsiveness of NPs enables specific payload release. Moreover, the macrophage membrane sequesters proinflammatory cytokines to suppress local inflammation. The synergistic effects of pharmacotherapy and inflammatory cytokines sequestration from such a biomimetic drug delivery system lead to improved therapeutic efficacy in atherosclerosis. Comparison to macrophage internalized with ROS-responsive NPs, as a live-cell based drug delivery system for treatment of atherosclerosis, suggests that cell membrane coated drug delivery approach is likely more suitable for dealing with an inflammatory disease than the live-cell approach.

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Section: Attenuation Effects Of Mm-at-nps On Inflammation In Vitromentioning

confidence: 99%

Treatment of atherosclerosis by macrophage-biomimetic nanoparticles via targeted pharmacotherapy and sequestration of proinflammatory cytokines

et al. 2020

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“…Following the trafficking of monocytes into arteries, these cells form foamy macrophages. This process is controlled by three pathways: the influx of modified lipoproteins, the biosynthesis of cholesteryl ester, and lipid efflux [17]. We tested aorta tissues for the markers representing these pathways.…”

Section: Inhibition Of Sphingolipid Synthesis Ameliorates Vascular LImentioning

confidence: 99%

Myriocin and d-PDMP ameliorate atherosclerosis in ApoE−/− mice via reducing lipid uptake and vascular inflammation

Peng

et al. 2020

Clinical Science

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Sphingolipids have been implicated in the etiology of atherosclerosis. The commonly used sphingolipid inhibitors, myriocin (a ceramide inhibitor) and d-PDMP (d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, a glycosphingolipid inhibitor), have shown therapeutic potential but their efficacy and their underlying mechanisms remain unclear. Here, apolipoprotein E-deficient (apoE−/−) mice were fed a high-fat diet (HFD) and treated with a control, myriocin, d-PDMP, or atorvastatin for 12 weeks. We analyzed the effects of these drugs on the size and detailed composition of atherosclerotic plaques. Molecular biological approaches were used to explore how the inhibitors affect lipid metabolism and foam-cell formation. Treatment with myriocin or d-PDMP led to smaller and less vulnerable atherosclerotic lesions and was almost as effective as atorvastatin. Sphingolipid inhibitors down-regulated the expression of monocyte chemotactic protein 1 (MCP-1) and its receptor chemoattractant cytokine receptor 2 (CCR2), which play a key role in monocyte recruitment. They also decreased pro-inflammatory Ly-6chigh monocytes and influenced the uptake of modified LDL by down-regulating the expression of cluster of differentiation 36 (CD36) and lectin-like oxidized LDL (ox-LDL) receptor-1 (LOX-1). The inhibitors exhibited the advantage of maintaining normal glucose homeostasis compared with atorvastatin. These findings reveal for the first time that the modulation of sphingolipid synthesis can effectively alleviate atherosclerosis progression by preventing lipid uptake and reducing inflammatory responses in the arterial walls.

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“…Along with the continuous formation and necrosis of the foam cells, regional in ammatory storm induced by excessive cytokines caused damage to the vessels [11]. OxLDL ingestion induced foam cells formation and soon afterwards, accelerated mitochondrial oxidative stress [12] , [13], which led to accumulating reactive oxygen species (ROS) production [13].Taken together, these factors evoked in ammatory response signaling pathway in foam cells [14,15]. In our previous studies, oxLDL activated pre-in ammatory signaling pathway and raised expression and secretion of in ammatory cytokines in VSMCs via Tlr4 [16].…”

Section: Introductionmentioning

confidence: 99%

Toll-Like Receptor 4 Mediated Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation in Vascular Smooth Muscle Cells

Chen

Xue

Cao

et al. 2020

Preprint

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Background: Oxidized low-density lipoprotein (oxLDL) induced a foam-cell like phenotype of the vascular smooth muscle cells (VSMCs), leading to the inflammatory responses incorporating Toll-like receptors (Tlrs)-mediated cellular alterations. We previously found that Tlr4 participated in inflammation response in VSMCs under oxLDL stimulation. However, the role of Tlr4 in foam-cell formation and underlying molecular pathways has not been comprehensively elucidated. This study aimed to investigate the role of Tlr4-mediated mechanisms in oxLDL induced foam-cell formation within VSMCs. Methods: After incubated with different dose of oxLDL, the lipid, reactive oxygen species (ROS) accumulation and foam-cell phenotype of the VSMCs were detected. The alteration of Tlr family, ROS and lipid accumulation regulators including the Src kinase, Nox2, Nox4, Mnsod and sirtuins were measured. Then the Tlr4 was knock down and underlying cellular change and altered molecules were detected. Results: We showed that oxLDL induced foam-cell like phenotype in VSMCs and led to lipid and ROS accumulation in a dose-dependent manner. OxLDL induced the strongest upregulation of Tlr4 in the Tlrs family and initiated change of Src activation, Nox2, Mnsod, sirt1 and sirt3 expression. The effect of oxLDL was abolished by Tlr4 knockdown. Furthermore, knocking down of Tlr4 reduced Src activation and led to restored Sirt1/Sirt3 expression. Moreover, inhibiting or knocking down the Src kinase diminished lipid accumulation in VSMCs under oxLDL treatment. And overexpression of Sirt1/3 relieved the oxLDL induced ROS accumulation and foam-cell phenotype in VSMCs.Conclusions: These results demonstrated that Tlr4 is a critical regulator in oxLDL induced foam cell formation of VSMCs via mediating Src kinase as well as Sirt1 and Sirt3. Beyond the role of Tlr4 in inflammation response of VSMCs, we provide an integrated mechanism about TLR4 in VSMCs phenotype transition under oxLDL stimulation.

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

Cited by 49 publications

References 37 publications

Treatment of atherosclerosis by macrophage-biomimetic nanoparticles via targeted pharmacotherapy and sequestration of proinflammatory cytokines

Treatment of atherosclerosis by macrophage-biomimetic nanoparticles via targeted pharmacotherapy and sequestration of proinflammatory cytokines

Myriocin and d-PDMP ameliorate atherosclerosis in ApoE−/− mice via reducing lipid uptake and vascular inflammation

Toll-Like Receptor 4 Mediated Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation in Vascular Smooth Muscle Cells

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