ScRNA-seq of atherosclerotic plaques of Apoe-/- mouse (with or without specific SMC KO of Has3)
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PROVIDER: PRJNA757834 | ENA |
REPOSITORIES: ENA
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Project description:We have applied 10X single-cell RNA sequencing (scRNA-seq) technique to examine the cell type specific transcriptomes of heterogeneous cell populations in atherosclerotic aortas isolated from Oasl1+/+Apoe-/- and Oasl1-/-Apoe-/- mice.
2022-09-06 | GSE186355 | GEO
Project description:To investigate the expression profiles of miRNA in atherosclerotic plaques, the global features of miRNAs expression of three normal coronary artery tissues sample pools and three sample pools of advanced atherosclerosis plaques of coronary artery were studied using microarray technology,
2015-02-20 | E-MTAB-2460 | biostudies-arrayexpress
Project description:Arsenic exposure is a global health problem and is correlated with adverse atherosclerotic outcomes in humans and in mouse models. However, the mechanisms of action are unclear. Since an atherosclerotic plaque is an amalgam of diverse immune and non-immune cells working in consortium, we set out to understand the mechanisms of arsenic-enhanced atherosclerosis in the CD45+ immune cells of atherosclerotic plaques in apoE-/- mouse model. To do this, we employ single-cell RNA- and single-cell-ATAC sequencings to understand both the genomic and epigenomic landscapes of these plaques.
2023-10-03 | GSE240753 | GEO
Project description:Background Rupture or erosion of advanced atherosclerotic lesions with a resultant myocardial infarction or stroke are the leading worldwide cause of death. However, we have a very limited understanding of the identity, origin, and function of many cells that make up late stage atherosclerotic lesions, as well as the mechanisms by which they control plaque stability. Methods and Results Using RNAseq and ChIPseq of advanced atherosclerotic lesions from mice, we provide evidence SMC-specific Klf4- versus Oct4-knockout ApoE-/- mice showed virtually opposite genomic signatures and putative SMC Klf4 or Oct4 target genes play an important role regulating SMC phenotypic changes. Further, we conducted a comprehensive single-cell RNA-seq of advanced human carotid endarterectomy samples and compared these with scRNAseq from murine micro-dissected advanced atherosclerotic lesions with SMC and endothelial lineage tracing to survey all plaque cell types and rigorously determine their origin. This analysis revealed remarkable similarity of transcriptomic clusters between mouse and human lesions and extensive plasticity of SMC- and EC-derived lesion cells. The latter included 7 distinct clusters of SMC- and EC-derived cells, most negative for traditional markers. In particular, SMC contributed to a Myh11-, Lgals3+ population with a chondrocyte-like gene signature that was markedly reduced with SMC-specific conditional knockout of Klf4. To study these cells and the mechanisms of their transition, we developed an innovative dual lineage tracing mouse that can uniquely label and genetically target Myh11+ SMC that subsequently activate Lgals3. We observed that SMC that activate Lgals3 comprise up to 2/3 of all SMC in advanced plaques. However, initial activation of Lgals3 in these cells does not represent conversion to a terminally differentiated state, but rather represents transition of these cells to a unique stem cell marker gene+, ECM-remodeling, “pioneer” cell phenotype that are the first to invest within lesions and subsequently give rise to at least 3 other SMC phenotypes within advanced lesions including Klf4-dependent osteogenic phenotypes likely to contribute to plaque calcification and plaque destabilization. Conclusions Taken together, these results provide evidence that SMC-derived cells within advanced mouse and human atherosclerotic lesions exhibit far greater phenotypic plasticity than generally believed, with Klf4 regulating transition to multiple phenotypes including Lgals3+ osteogenic cells likely to be detrimental for late stage atherosclerosis plaque pathogenesis.
2020-07-23 | GSE150644 | GEO
Project description:Macrophages represent a major immune cell population in atherosclerotic plaques and play central role in the progression of this lipid-driven chronic inflammatory disease. Targeting immunometabolism is proposed as a strategy to revert aberrant macrophage activation to improve disease outcome. Here, we show ATP citrate lyase (Acly) to be activated in inflammatory macrophages and human atherosclerotic plaques. We demonstrate that myeloid Acly deficiency induces a stable plaque phenotype characterized by increased collagen deposition and fibrous cap thickness, along with a smaller necrotic core. In-depth functional, lipidomic, and transcriptional characterization indicate deregulated fatty acid and cholesterol biosynthesis and reduced liver X receptor (LXR) activation within the macrophages in vitro. This results in macrophages that are more prone to undergo apoptosis, whilst presenting increased phagocytosis of apoptotic cells. Together, our results indicate that targeting macrophage metabolism improves atherosclerosis outcome and we reveal Acly as a promising therapeutic target to stabilize atherosclerotic plaques.
2020-02-18 | GSE126690 | GEO
Project description:Macrophages represent a major immune cell population in atherosclerotic plaques and play central role in the progression of this lipid-driven chronic inflammatory disease. Targeting immunometabolism is proposed as a strategy to revert aberrant macrophage activation to improve disease outcome. Here, we show ATP citrate lyase (Acly) to be activated in inflammatory macrophages and human atherosclerotic plaques. We demonstrate that myeloid Acly deficiency induces a stable plaque phenotype characterized by increased collagen deposition and fibrous cap thickness, along with a smaller necrotic core. In-depth functional, lipidomic, and transcriptional characterization indicate deregulated fatty acid and cholesterol biosynthesis and reduced liver X receptor activation within the macrophages in vitro. This results in macrophages that are more prone to undergo apoptosis, whilst maintaining their capacity to phagocytose apoptotic cells. Together, our results indicate that targeting macrophage metabolism improves atherosclerosis outcome and we reveal Acly as a promising therapeutic target to stabilize atherosclerotic plaques.
2021-03-05 | MTBLS2159 | MetaboLights
Project description:We compared gene expression profiles between asymptomatic and symptomatic atherosclerotic plaques from the same patient. This was accomplished by analyzing carotid plaques from four patients with bilateral high-grade carotid artery stenoses one being symptomatic (TIA or stroke) and the other asymptomatic.
2006-02-10 | E-MEXP-268 | biostudies-arrayexpress
Project description:In order to identify potential new biomarkers of atherosclerotic plaque composition we performed a large scale analysis of gene expression patterns in human atherosclerotic lesions. Whole genome expression analysis of 101 peripheral plaques identified a robust gene signature (1514 genes) dominated by inflammatory processes, and cholesterol metabolism and storage genes. Specific pathways enriched in this signature included activation of the Toll-like receptor signaling pathway, T-cell activation, cholesterol efflux, oxidative stress response, inflammatory cytokine production, vasoconstriction and lysosomal activity. Analysis of gene expression in plaque micro-dissected material revealed that the signature is strongly up-regulated in macrophage-rich regions and down-regulated in regions with high smooth muscle cell content. A smaller qPCR biomarker panel and inflammatory composite score (ICS) were developed to facilitate clinical translation of discoveries from gene expression profiling. We found that ICS correlates with histological features related to plaque vulnerability. In addition, ICS is able to separate groups of plaques obtained from symptomatic and asymptomatic patients undergoing carotid endarerectomy. In summary, we identified a robust mRNA biomarker panel associated with histo-pathological as well as clinical hallmarks of vulnerable atherosclerotic plaque. This panel may be used as a diagnostic and prognostic tool in clinical setting to evaluate novel anti-atherosclerotic therapies. 290 human peripheral plaques were excised using the FoxHollow silverhawk catheter and stored in RNAlater. RNA was extracted, amplified and hybridized to Affymetrix/Merck custom 1.0 arrays (GPL10687).
2011-09-30 | E-GEOD-24702 | biostudies-arrayexpress
Project description:In order to identify potential new biomarkers of atherosclerotic plaque composition we performed a large scale analysis of gene expression patterns in human atherosclerotic lesions. Whole genome expression analysis of 101 peripheral plaques identified a robust gene signature (1514 genes) dominated by inflammatory processes, and cholesterol metabolism and storage genes. Specific pathways enriched in this signature included activation of the Toll-like receptor signaling pathway, T-cell activation, cholesterol efflux, oxidative stress response, inflammatory cytokine production, vasoconstriction and lysosomal activity. Analysis of gene expression in plaque micro-dissected material revealed that the signature is strongly up-regulated in macrophage-rich regions and down-regulated in regions with high smooth muscle cell content. A smaller qPCR biomarker panel and inflammatory composite score (ICS) were developed to facilitate clinical translation of discoveries from gene expression profiling. We found that ICS correlates with histological features related to plaque vulnerability. In addition, ICS is able to separate groups of plaques obtained from symptomatic and asymptomatic patients undergoing carotid endarerectomy. In summary, we identified a robust mRNA biomarker panel associated with histo-pathological as well as clinical hallmarks of vulnerable atherosclerotic plaque. This panel may be used as a diagnostic and prognostic tool in clinical setting to evaluate novel anti-atherosclerotic therapies. Total RNA from peripheral plaque (n=101) profiled in the Merck/Agilent 44k v1.1 against a reference pool of total RNA from 7 carotid plaques.
2011-09-30 | E-GEOD-23304 | biostudies-arrayexpress
Project description:Clonal hematopoiesis (CH) is an independent risk factor for atherosclerotic cardiovascular disease. Murine models of CH suggest a central role of inflammasomes and IL-1β in accelerated atherosclerosis and plaque destabilization. Here we show using scRNAseq in human carotid plaques that inflammasome components are enriched in macrophages, while the receptor for IL-1β is enriched in fibroblasts and smooth muscle cells (SMCs). To address the role of inflammatory crosstalk in features of plaque destabilization, we conducted SMC fate mapping in mice modeling Jak2VF or Tet2 CH treated with IL-1β antibodies. Unexpectedly, this treatment minimally affected SMC differentiation, leading instead to a prominent expansion of fibroblast-like cells. Depletion of fibroblasts from mice treated with IL-1β antibody resulted in thinner fibrous caps. Conversely, genetic inactivation of Jak2VF during plaque regression promoted fibroblasts accumulation and fibrous cap thickening. Our studies suggest that suppression of inflammasomes promotes plaque stabilization by recruiting fibroblast-like cells to the fibrous cap.
2023-11-25 | GSE248394 | GEO