Targeting netrin-1 in established atherosclerosis promotes inflammation resolution and plaque regression
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE168389 | GEO | 2021/10/27
REPOSITORIES: GEO
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Project description:Targeting netrin-1 in established atherosclerosis promotes inflammation resolution and plaque regression
| PRJNA707203 | ENA
Project description:We have carried out a systems biology investigation of regulators controlling arterial plaque macrophage transcriptional changes in response to lipid lowering, in the Reversa mouse model of plaque regression in which poly I:C injections induce recombination-mediated inactivation of Mttp in the liver and (when combined with a switch to chow diet) restore normal lipid levels in an Ldlr-/-Apob100/100 mouse (Lieu et al., 2003, Circulation, v.107(9), pp.1315-21). Twenty-four Reversa mice (12 males, 12 females) were maintained on Western diet for 16 weeks and given injections of either poly I:C or vehicle (saline) and then switched to normal chow. At seven days after the last injection, animals were sacrificed and CD68+ macrophages were isolated from the aortic root plaque using laser-capture microdissection. An additional two Ldlr-/- animals (male) were treated with poly I:C and CD68+ aortic root plaque macrophages were obtained, as a control group for effects of poly I:C independent of Mttp inactivation. RNA isolated from each of the 26 samples was reverse-transcribed, amplified, fragmented, labeled, and then hybridized to the Affymetrix Mouse Exon Array 1.0 ST GeneChip. Probe intensities were analyzed using transcript-level probesets for gene expression profiling, and for each mouse transcript represented on the microarray, a two-factor model (sex and treatment) was used for the analysis of the 24 samples from the Reversa mice, to test for a significant effect of the poly I:C (vs. saline) treatment.
2014-12-04 | GSE52482 | GEO
Project description:Regression of atherosclerosis is an important clinical goal, however the pathways that mediate the resolution of atherosclerotic inflammation and reversal of plaques are poorly understood. Regulatory T cells (Tregs) have been shown to be atheroprotective, however numbers of these immunosuppressive cells decrease with disease progression. Using multiple independent mouse models of atherosclerosis regression, we demonstrate that an increase in plaque Tregs is a common signature of regressing plaques. To test if Tregs are required for the resolution of atherosclerotic inflammation and plaque regression during lipid-lowering therapy, we combined CD25 monoclonal antibody (PC61 mAb)-mediated Treg depletion with single-cell RNA-sequencing of immune cells in the plaque and conventional analyses of atherosclerosis. Single cell RNA-sequencing revealed that Tregs from aortic plaques shared some similarity with splenic Tregs, but were distinct from skin and colon Tregs supporting recent findings of tissue-dependent Treg heterogeneity. Furthermore, Tregs from progressing plaques expressed markers of natural Tregs derived from the thymus, whereas Tregs in regressing plaques lacked Nrp1 and Helios expression, suggesting that they are induced in the periphery during lipid lowering. Treatment of atherosclerotic mice with PC61 mAb effectively depleted Tregs in the blood and peripheral tissues, including plaques, and blocked the regression of atherosclerosis induced by apoB anti-sense oligonucleotides. Morphometric analyses revealed that control antibody-treated mice showed a 40% decrease in plaque burden and macrophage content under regression conditions, whereas PC61 mAb-treated mice showed no change in plaque size or inflammatory cell content compared to baseline. Moreover, Treg depletion enhanced inflammatory signaling and blocked tissue reparative functions of macrophages in the regressing plaque, including M2-polarization, efferocytosis and sensing of specialized pro-resolving lipid mediators. Together, these data establish essential roles for Tregs in the resolution of atherosclerotic inflammation and plaque remodeling during regression.
2020-07-22 | GSE141038 | GEO
Project description:Plaque calcification develops by the inflammation-dependent mechanisms involved in progression and regression of atherosclerosis. Macrophages can undergo two distinct polarization states, that is, pro-inflammatory M1 phenotype in progression and anti-inflammatory M2 phenotype in regression. In plaque progression, predominant M1 macrophages promote the initial calcium deposition within the necrotic core of the lesions, called as microcalcification, through not only vesicle-mediated mineralization as the result of apoptosis of macrophages and vascular smooth muscle cells (VSMCs), but also VSMC differentiation into early phase osteoblasts. On the other hand, in plaque regression M2 macrophages are engaged in the healing response to plaque inflammation. In association with the resolution of chronic inflammation, M2 macrophages may facilitate macroscopic calcium deposition, called as macrocalcification, through induction of osteoblastic differentiation and maturation of VSMCs. Oncostatin M, which has been shown to promote osteoblast differentiation in bone, may play a pivotal role in the development of plaque calcification. Clinically, two types of plaque calcification have distinct implications. Macrocalcification leads to plaque stability, while microcalcification is more likely to be associated with plaque rupture. Statin therapy, which reduces cardiovascular mortality, has been shown to exert its dual actions on plaque morphology, that is, regression of atheroma and increment of macroscopic calcium deposits. Statins may facilitate the healing process against plaque inflammation by enhancing M2 polarization of macrophages. Vascular calcification has pleiotropic properties as pro-inflammatory "microcalcification" and anti-inflammatory "macrocalcification". The molecular mechanisms of this process in relation with plaque progression as well as plaque regression should be intensively elucidated.
| S-EPMC5906181 | biostudies-other
Project description:Floor plate-derived extracellular signaling molecules, including canonical axon guidance cues of the Netrin family, control neuronal circuit organization. Despite the importance of the floor plate as an essential signaling centre in the developing vertebrate central nervous system, no systematic approach to identify binding partners for floor plate-expressed cellsurface and secreted proteins has been carried out. Here, we used a high-throughput assay to discover extracellular protein-protein interactions, which likely take place in the zebrafish floor plate microenvironment. The assembled floor plate network contains 47 interactions including the hitherto not reported interaction between Netrin-1 and Draxin. We further characterized this interaction, narrowed down the binding interface, and demonstrated that Draxin competes with Netrin receptors for binding to Netrin-1. Our results suggest that Draxin functions as an extracellular Netrin signaling modulator in vertebrates. A reciprocal gradient of Draxin might shape or sharpen the active Netrin gradient, thereby critically modulating its effect.
2015-05-31 | E-MTAB-3609 | biostudies-arrayexpress
Project description:Atherosclerotic plaques belong to the common vascular disease in the aged, which rupture will lead to acute thromboembolic diseases, the major reason for fatal cardiovascular events. Accumulating evidence indicates that lncRNAs exert critical functions in atherosclerosis. To identify novel astherosclerotic plaques-relevant lncRNAs, four specimens of carotid atherosclerotic plaque were collected, and endovascular tissue one centimeter far from the carotid atherosclerotic plaque was taken as a control group, we performed lncRNA microarray analysis using Affymetrix Human OElncRNA
2022-07-01 | GSE207252 | GEO
Project description:The generation of induced pluripotent stem (iPS) cells holds great promise in regenerative medicine. However, the relative flaws in the understanding of the molecular mechanisms promoting or limiting reprogramming still hinder the efficient generation of high quality iPS cells. Whereas modulation of the initial Oct4, Sox2, Klf4 and c-Myc (OSKM) cocktail with new transcription factors has been extensively documented, comparatively little is known about soluble molecules promoting the process, even if such recombinant factors could be highly valuable for therapeutic applications. In this study we developed a large-scale identification method to uncover novel programmed cell death (PCD)-related mechanisms limiting somatic cell reprogramming to pluripotency (SCRP). We identified Netrin-1 and its dependence receptor Dcc (Deleted in Colorectal Carcinoma), previously described for their respective survival/death functions both in normal and oncogenic contexts, as novel key SCRP modulators. We show that the early phase of SCRP is accompanied with a strong Netrin-1 deficiency, due to the improper epigenetic regulation of the Ntn1 promoter by OSKM. Mechanistically, we demonstrate that such Netrin-1 imbalance induces apoptosis mediated by the dependence receptor Dcc in a p53-independent manner. Correction of the Netrin-1/Dcc equilibrium by gain-of-ligand and loss-of-receptor experiments constrains apoptosis and improves reprogramming. As a consequence, we propose a novel iPS derivation protocol including a sequential treatment with recombinant Netrin1 that greatly facilitates the generation of mouse and human iPS cells. RNA-sequencing of mouse embryonic fibroblasts (passage 2 and passage 4), mouse pre-iPS cells (passage 5 and passage 25), 1 clone of control iPS (passage 5 and passage 25) and 2 independent clones of "Netrin-1 derived" iPS cells (passage 5 and passage 25). For this analysis, mouse iPS cell lines were grown in KSR+LIF media.
2015-09-01 | E-GEOD-54107 | biostudies-arrayexpress
Project description:Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol levels. Despite ongoing advances in the prevention and treatment of atherosclerosis 1, cardiovascular disease remains the leading cause of death worldwide 2. Continuous retention of apolipoprotein B-containing lipoproteins in the subendothelial space causes a local overabundance of free cholesterol. Since cholesterol accumulation and deposition of cholesterol crystals (CCs) triggers a complex inflammatory response 3 4, we tested the therapeutic potential of increasing cholesterol solubility in experimental atherogenesis. Here we show that treatment of murine atherosclerosis with the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (CD), a compound that solubilizes lipophilic substances, reduced atherosclerotic plaque size, cholesterol crystal load and promoted plaque regression even under continuing Western diet. CD solubilized CCs and promoted cholesterylester and oxysterol production in macrophages leading to liver X receptor (LXR)-mediated transcriptional reprogramming. CD increased cholesterol efflux from macrophages and substantially augmented reverse cholesterol transport in vivo. Furthermore, CD reduced proinflammatory cytokines in vivo and decreased macrophage responsiveness towards TLR and inflammasome activation. Since CD treatment in humans is safe and CD beneficially affects key pathogenetic factors in atherogenesis it may thus be used clinically to prevent or treat human atherosclerosis .
2016-05-06 | GSE67011 | GEO
Project description:Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol levels. Despite ongoing advances in the prevention and treatment of atherosclerosis 1, cardiovascular disease remains the leading cause of death worldwide 2. Continuous retention of apolipoprotein B-containing lipoproteins in the subendothelial space causes a local overabundance of free cholesterol. Since cholesterol accumulation and deposition of cholesterol crystals (CCs) triggers a complex inflammatory response 3 4, we tested the therapeutic potential of increasing cholesterol solubility in experimental atherogenesis. Here we show that treatment of murine atherosclerosis with the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (CD), a compound that solubilizes lipophilic substances, reduced atherosclerotic plaque size, cholesterol crystal load and promoted plaque regression even under continuing Western diet. CD solubilized CCs and promoted cholesterylester and oxysterol production in macrophages leading to liver X receptor (LXR)-mediated transcriptional reprogramming. CD increased cholesterol efflux from macrophages and substantially augmented reverse cholesterol transport in vivo. Furthermore, CD reduced proinflammatory cytokines in vivo and decreased macrophage responsiveness towards TLR and inflammasome activation. Since CD treatment in humans is safe and CD beneficially affects key pathogenetic factors in atherogenesis it may thus be used clinically to prevent or treat human atherosclerosis .
2016-05-06 | GSE67013 | GEO
Project description:Background: Using proteomics, we strove to reveal novel molecular subtypes of human atherosclerotic lesions, study their associations with histology and imaging and relate them to long-term cardiovascular outcomes. Methods: 219 samples were obtained from 120 patients undergoing carotid endarterectomy. Sequential protein extraction was combined with multiplexed, discovery proteomics. Parallel reaction monitoring for 135 proteins was deployed for targeted validation. A combination of statistical, bioinformatics and machine learning methods was used to perform differential expression, network, pathway enrichment analysis and train and evaluate prognostic models. Results: Our extensive proteomics analysis from the core and periphery of plaques doubled the coverage of the plaque proteome compared to the largest proteomics study on atherosclerosis thus far. Plaque inflammation and calcification signatures were inversely correlated and validated with targeted proteomics. The inflammation signature was enriched with neutrophil-derived proteins, including calprotectin (S100A8/9) and myeloperoxidase. The calcification signature contained fetuin-A, osteopontin, and gamma-carboxylated proteins. Sex differences in the proteome of atherosclerosis were explained by a higher proportion of calcified plaques in women. Single-cell RNA sequencing data attributed the inflammation signature predominantly to neutrophils and macrophages and the calcification signature to smooth muscle cells, except for certain plasma proteins that were not expressed but retained in the plaque, i.e., fetuin-A. Echogenic lesions reflect the collagen content and calcification of plaque but carotid Duplex ultrasound fails to capture the extent of inflammatory protein changes in symptomatic plaques. Applying dimensionality reduction and machine learning on the proteomics data defined 4 distinct plaque phenotypes and revealed key protein signatures linked to smooth muscle cell content, plaque calcification and structural extracellular matrix, which improved the 9-year prognostic AUC by 25% compared to ultrasound and histology. A biosignature of four proteins (CNN1, PROC, SERPH, and CSPG2) independently predicted the progression of atherosclerosis and cardiovascular mortality with an AUC of 75% Conclusion: We combined discovery and targeted proteomics with network reconstruction and clustering techniques to provide molecular insights into protein changes in atherosclerotic plaques. The application of proteomics and machine learning techniques revealed distinct clusters of plaques that inform on disease progression and future adverse cardiovascular events.
2023-11-15 | PXD031052 | Pride