Targeting netrin-1 in established atherosclerosis promotes inflammation resolution and plaque regression
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PROVIDER: PRJNA707203 | ENA |
REPOSITORIES: ENA
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Project description:We used single cell RNA-sequencing of aortic CD45+ leukocytes, combined with immunohistologic, morphometric and flow cytometric analyses to define the changes in plaque immune cell composition and to define the immunological landscpape changes following the deletion of netrin-1
2021-10-27 | GSE168389 | 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:Atherosclerosis is the leading underlying cause of death worldwide. We reported a mouse model of atherosclerosis regression that involves transplanting an atherosclerotic aortic arch into a normolipidemic mouse. There, emigration of plaque foam cells occurred in a CCR7 (dendritic cell migration factor) dependent manner. It was obvious, though, that other pathways are likely to be involved in this process. We therefore performed microarrays on laser captured macrophages isolated from the progression and regression environments. This yielded two major findings. Firstly, genes associated with the contractile apparatus (such as actin and myosin) that are responsible for cellular movement were differentially up-regulated under regression conditions with members of the cadherin family (serves in adhesion functions) being significantly down-regulated. Secondly, the most highly up-regulated gene under regression was arginase I, a classical marker of the M2 alternative activated macrophage. Further examination revealed that regression was characterized by macrophages displaying other M2 markers such as CD163, C-lectin receptor, mannose receptor, and Fizz-1. In addition, we applied recently introduced local causal pathway discovery methods to our microarray data that revealed that genes such as vinculin and ApoCII may play a role in the pathophysiology of atherosclerosis regression. Ultimately, the insights gained from the regression model and the different modes of analyses should lead to new therapeutic targets against cardiovascular disease. We performed microarrays on laser captured macrophages isolated from aortic arch from mouse in atherosclerosis progression and regression environments (C57Bl/6, ApoE -/-). Study was performed in two batches, with three treatment groups each: progression, regression and baseline. Profiled in the Merck/Agilent 3.0
2011-09-30 | E-GEOD-24819 | biostudies-arrayexpress
Project description:The goal of this study is to determine whether PRMT2 plays a causal role in the impairment of atherosclerosis regression in diabetes. We examined the consequence of deleting PRMT2 in myeloid cells during the regression of atherosclerosis in normal and diabetic mice. We found significant impairment of atherosclerosis regression under normoglycemic conditions in mice lacking PRMT2 (Prmt2-/-) in myeloid cells that mimic the decrease in regression of atherosclerosis in WT mice under diabetic conditions. This was associated with increased plaque macrophage retention. PRMT2-deficient plaque CD68+ cells under normoglycemic conditions showed increased expression of genes involved in cytokine signaling and inflammation compared to WT cells by RNA seq. Thus, the loss of PRMT2 is causally linked to impaired atherosclerosis regression.
2022-07-20 | GSE203523 | GEO
Project description:Atherosclerosis is the leading underlying cause of death worldwide. We reported a mouse model of atherosclerosis regression that involves transplanting an atherosclerotic aortic arch into a normolipidemic mouse. There, emigration of plaque foam cells occurred in a CCR7 (dendritic cell migration factor) dependent manner. It was obvious, though, that other pathways are likely to be involved in this process. We therefore performed microarrays on laser captured macrophages isolated from the progression and regression environments. This yielded two major findings. Firstly, genes associated with the contractile apparatus (such as actin and myosin) that are responsible for cellular movement were differentially up-regulated under regression conditions with members of the cadherin family (serves in adhesion functions) being significantly down-regulated. Secondly, the most highly up-regulated gene under regression was arginase I, a classical marker of the M2 alternative activated macrophage. Further examination revealed that regression was characterized by macrophages displaying other M2 markers such as CD163, C-lectin receptor, mannose receptor, and Fizz-1. In addition, we applied recently introduced local causal pathway discovery methods to our microarray data that revealed that genes such as vinculin and ApoCII may play a role in the pathophysiology of atherosclerosis regression. Ultimately, the insights gained from the regression model and the different modes of analyses should lead to new therapeutic targets against cardiovascular disease.
2011-10-01 | GSE24819 | GEO
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: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:Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol levels. Since cholesterol retention and cholesterol crystals in arterial walls are key pathogenetic factors for atherogenesis, we assessed the therapeutic potential of increasing cholesterol solubility in vivo. 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 (CC) load and promoted plaque regression even under continuing Western diet. CD solubilized CC and promoted cholesterylester and oxysterol production in macrophages leading to liver X receptor-mediated transcriptional reprogramming with increased cholesterol efflux and decreased inflammation. CD treatment may thus be used to increase cholesterol solubility and clearance to prevent or treat atherosclerosis.
2017-07-01 | GSE47696 | GEO
Project description:Neutrophil extracellular traps (NETs) promote inflammation and atherosclerosis progression. In diabetes they are increased and impair wound healing, during which inflammation normally resolves. Atherosclerosis regression, a process resembling wound healing, is also impaired in diabetes. Thus, we hypothesized that NETs impede atherosclerosis regression in diabetes through unresolved inflammation. Objective: To investigate in diabetes the effect of NETs on plaque macrophage inflammation and whether NETs reduction improves atherosclerosis regression. Findings: Transcriptomic profiling of plaque macrophages from NET positive and negative areas in Ldlr-/- mice revealed inflammasome and glycolysis pathway upregulation, indicating a pro-inflammatory phenotype. During atherosclerosis regression in non-diabetic mice, plaque NET content decreased. In contrast, in diabetic mouse plaques NETs were enriched and persisted after lipid-lowering. DNase1 treatment (to degrade NETs) of diabetic mice reduced plaque NETs and macrophage inflammation and improved atherosclerosis regression after lipid-lowering. Conclusions: NETs decline during atherosclerosis regression in non-diabetic mice, but persist in diabetes and impair regression by exacerbating macrophage inflammation. DNase1 reduced diabetic plaque NETs and macrophage inflammation, and restored atherosclerosis resolution after lipid-lowering, despite ongoing hyperglycemia. Given that humans with diabetes also exhibit impaired atherosclerosis resolution with lipid-lowering, these data suggest that NETs contribute to the increased CVD risk in this population.
2020-05-12 | GSE145200 | GEO