Myeloid Tribbles 1 induces early atherosclerosis via enhanced foam cell expansion

Johnston, Jessica; Angyal, Adrienn; Bauer, Robert C.; Hamby, Stephen E.; Suvarna, S K; Baidžajevas, Kajus; Hegedűs, Zoltán; Dear, T. Neil; Turner, Martin; Wilson, Heather L.; Goodall, Alison H.; Rader, Daniel J.; Shoulders, Carol C.; Francis, Sheila; Kiss-Tóth, Endre

doi:10.1126/sciadv.aax9183

Cited by 44 publications

(48 citation statements)

References 40 publications

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“…Foam cell formation, induced by phagocytizing LDL-C and ox-LDL by macrophages in the early atherosclerotic plaques, is an important factor in the development of AS [22]. In order to establish a macrophage-derived foam cell model, we cultured RAW264.7 cells with different concentrations of ox-LDL.…”

Section: Resultsmentioning

confidence: 99%

Quercetin Suppresses the Progression of Atherosclerosis by Regulating MST1-Mediated Autophagy in ox-LDL-Induced RAW264.7 Macrophage Foam Cells

Cao

Jia

et al. 2019

IJMS

116

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Objective: To investigate the process by which quercetin suppresses atherosclerosis by upregulating MST1-mediated autophagy in RAW264.7 macrophages. Methods: An in vitro foam cell model was established by culturing RAW264.7 macrophages with oxidized low-density lipoprotein (ox-LDL). The cells were treated with quercetin alone or in combination with the autophagy inhibitor, 3-methyladenine, and autophagy agonist, rapamycin. Cell viability was detected with a CCK-8 kit. Lipid accumulation was detected by oil red O staining, senescence was detected by SA-β-gal (senescence-associated β-galactosidase) staining, reactive oxygen species were detected by ROS assay kit. Autophagosomes and mitochondria were detected by transmission electron microscope (TEM), and expression of MST1, LC3-II/I, Beclin1, Bcl-2, P21, and P16 were detected by immunofluorescence and Western blot. Results: Ox-LDL induced RAW264.7 macrophage-derived foam cell formation, reduced survival, aggravated cell lipid accumulation, and induced a senescence phenotype. This was accompanied by decreased formation of autophagosome; increased expression of P53, P21, and P16; and decreased expression of LC3-II/I and Beclin1. After intervention with quercetin, the cell survival rate was increased, and lipid accumulation and senescence phenotype were reduced. Furthermore, the expression of LC3-II/I and Beclin1 were increased, which was consistent with the ability of quercetin to promote autophagy. Ox-LDL also increased the expression of MST1, and this increase was blocked by quercetin, which provided a potential mechanism by which quercetin may protect foam cells against age-related detrimental effects. Conclusion: Quercetin can inhibit the formation of foam cells induced by ox-LDL and delay senescence. The mechanism may be related to the regulation of MST1-mediated autophagy of RAW264.7 cells.

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Section: Resultsmentioning

confidence: 99%

Quercetin Suppresses the Progression of Atherosclerosis by Regulating MST1-Mediated Autophagy in ox-LDL-Induced RAW264.7 Macrophage Foam Cells

Cao

Jia

et al. 2019

IJMS

116

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“…Myeloid specific Trib1 over-expressor transgenic mice were generated by crossing Rosa26.Trib1 mice with Lyz2Cre recombinase transgenic mice as described above. The resulting mice; Rosa26.Trib1 x Lyz2Cre (Trib1 mTg ) over-express Trib1 transgene by~2.5 fold as previously described by Johnston et al (9). Wild-type litter mates (Trib1 mWT ) were used as controls.…”

Section: Animal Experimentsmentioning

confidence: 99%

“…We first determined the effect of myeloid-specific Trib1 overexpression and KO on tissue-resident macrophage numbers and phenotype, employing wild-type (WT) and myeloid-specific Trib1 knock-out and Trib1 transgenic (Tg) mice. The generation and characterization of these strains has been reported previously (9). First, we wanted to ascertain the consequences of altered myeloid Trib1 levels in metabolic tissues as this gene has been identified as a risk locus for hyperlipidaemia in a number of GWAS analyses (29-31) but its molecular mechanism impacting on lipid homeostasis is still incompletely understood.…”

Section: Manipulation Of Trib1 Expression Alters Liver and Adipose Timentioning

confidence: 99%

“…However, through the pseudokinase domain, TRIB1 acts as adapter or scaffold facilitating assembly with other proteins (2)(3)(4). TRIB1 is an established oncogene in acute myeloid leukemia (5,6) and has been shown to play a pivotal role in the differentiation of anti-inflammatory M2-macrophages in the pathogenesis of early atherosclerosis and during adipose tissue inflammation (7)(8)(9). Additionally, TRIB1 has been reported to be overexpressed in prostate cancer, where it controls the expression of endoplasmic reticulum chaperone proteins and induces M2-macrophage differentiation (10,11).…”

Section: Introductionmentioning

confidence: 99%

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Tribbles-1 Expression and Its Function to Control Inflammatory Cytokines, Including Interleukin-8 Levels are Regulated by miRNAs in Macrophages and Prostate Cancer Cells

et al. 2020

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The pseudokinase TRIB1 controls cell function in a range of contexts, by regulating MAP kinase activation and mediating protein degradation via the COP1 ubiquitin ligase. TRIB1 regulates polarization of macrophages and dysregulated Trib1 expression in murine models has been shown to alter atherosclerosis burden and adipose homeostasis. Recently, TRIB1 has also been implicated in the pathogenesis of prostate cancer, where it is often overexpressed, even in the absence of genetic amplification. Well described TRIB1 effectors include MAP kinases and C/EBP transcription factors, both in immune cells and in carcinogenesis. However, the mechanisms that regulate TRIB1 itself remain elusive. Here, we show that the long and conserved 3’untranslated region (3’UTR) of TRIB1 is targeted by miRNAs in macrophage and prostate cancer models. By using a systematic in silico analysis, we identified multiple “high confidence” miRNAs potentially binding to the 3’UTR of TRIB1 and report that miR-101-3p and miR-132-3p are direct regulators of TRIB1 expression and function. Binding of miR-101-3p and miR-132-3p to the 3’UTR of TRIB1 mRNA leads to an increased transcription and secretion of interleukin-8. Our data demonstrate that modulation of TRIB1 by miRNAs alters the inflammatory profile of both human macrophages and prostate cancer cells.

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“…Macrophages engulf Ox-LDL through its scavenger receptors and the accumulation of Ox-LDL into macrophages gives it a morphologic appearance of soap bubbles termed as foam cells which later result in atherosclerotic lesions leading to atherosclerotic plaque build-up, limiting the blood flow to the heart muscle (see Figure 1 for schematic diagram) [ 29 , 30 ]. Very recently, a study was published providing insights into myeloid tribbles 1 that induces early atherosclerosis via extensive foam cell formation [ 31 ]. A native LDL cannot exert atherogenic mechanisms in vitro which implicate that to be pathogenic it must have been modified, explaining oxidative damage as a pro [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Insights into the Oxidized Low-Density Lipoprotein-Induced Atherosclerosis

Khatana

Saini

Chakrabarti

et al. 2020

Oxidative Medicine and Cellular Longevity

257

105

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Dyslipidaemia has a prominent role in the onset of notorious atherosclerosis, a disease of medium to large arteries. Atherosclerosis is the prime root of cardiovascular events contributing to the most considerable number of morbidity and mortality worldwide. Factors like cellular senescence, genetics, clonal haematopoiesis, sedentary lifestyle-induced obesity, or diabetes mellitus upsurge the tendency of atherosclerosis and are foremost pioneers to definitive transience. Accumulation of oxidized low-density lipoproteins (Ox-LDLs) in the tunica intima triggers the onset of this disease. In the later period of progression, the build-up plaques rupture ensuing thrombosis (completely blocking the blood flow), causing myocardial infarction, stroke, and heart attack, all of which are common atherosclerotic cardiovascular events today. The underlying mechanism is very well elucidated in literature but the therapeutic measures remains to be unleashed. Researchers tussle to demonstrate a clear understanding of treating mechanisms. A century of research suggests that lowering LDL, statin-mediated treatment, HDL, and lipid-profile management should be of prime interest to retard atherosclerosis-induced deaths. We shall brief the Ox-LDL-induced atherogenic mechanism and the treating measures in line to impede the development and progression of atherosclerosis.

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Myeloid Tribbles 1 induces early atherosclerosis via enhanced foam cell expansion

Abstract: Trib1 controls atherosclerotic plaque macrophage function by up-regulating OLR1, promoting foam cell formation and atherosclerosis.

Cited by 44 publications

References 40 publications

Quercetin Suppresses the Progression of Atherosclerosis by Regulating MST1-Mediated Autophagy in ox-LDL-Induced RAW264.7 Macrophage Foam Cells

Quercetin Suppresses the Progression of Atherosclerosis by Regulating MST1-Mediated Autophagy in ox-LDL-Induced RAW264.7 Macrophage Foam Cells

Tribbles-1 Expression and Its Function to Control Inflammatory Cytokines, Including Interleukin-8 Levels are Regulated by miRNAs in Macrophages and Prostate Cancer Cells

Mechanistic Insights into the Oxidized Low-Density Lipoprotein-Induced Atherosclerosis

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