The environment-sensing aryl-hydrocarbon receptor inhibits the chondrogenic fate of modulated smooth muscle cells in atherosclerotic lesions
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA633538 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11806863_1.fastq.gz | Fastqsanger.gz | |||
| SRR11806863_2.fastq.gz | Fastqsanger.gz | |||
| SRR11806864_1.fastq.gz | Fastqsanger.gz | |||
| SRR11806864_2.fastq.gz | Fastqsanger.gz | |||
| SRR11806865_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 68 |
Similar Datasets
Project description:Aryl-hydrocarbon receptor protects against endochondral ossification of modulated smooth muscle cells in atherosclerosis Introduction: Smooth muscle cells (SMC) play a critical role in atherosclerosis. The Aryl hydrocarbon receptor (AHR) is an environment-sensing transcription factor that contributes to vascular development, and has been implicated in coronary artery disease (CAD) risk. We hypothesized that AHR can affect atherosclerosis by regulating phenotypic modulation of SMC. Methods: We combined RNA-Seq, ChIP-Seq, ATAC-Seq and in-vitro assays in human coronary artery SMC (HCASMC), with single-cell RNA-Seq (scRNA-Seq), histology, and RNAscope in an SMC-specific lineage-tracing Ahr knockout mouse model of atherosclerosis to better understand the role of AHR in vascular disease. Results: Genomic studies coupled with functional assays in cultured HCASMC revealed that AHR modulates HCASMC phenotype and suppresses ossification in these cells. Lineage tracing and activity tracing studies in the mouse aortic sinus showed that the Ahr pathway is active in modulated SMC in the atherosclerotic lesion cap. Furthermore, scRNA-Seq studies of the SMC-specific Ahr knockout mice showed a significant increase in the proportion of modulated SMC expressing chondrocyte markers such as Col2a1 and Alpl, which localized to the lesion neointima. These cells, which we term chondromyocytes (CMC), were also identified in the neointima of human coronary arteries. In histological analyses, these changes manifested as larger lesion size, increased lineage-traced SMC participation in the lesion, decreased lineage-traced SMC in the lesion cap, and increased alkaline phosphatase activity in lesions in the Ahr knockout compared to wild-type mice. We propose that AHR is likely protective based on these data and inference from human genetic analyses. Conclusion: Overall, we conclude that AHR promotes maintenance of lesion cap integrity and diminishes the disease related SMC-to-CMC transition in atherosclerotic tissues.
2020-07-01 | GSE150768 | GEO
Project description:BackgroundSmooth muscle cells (SMC) play a critical role in atherosclerosis. The Aryl hydrocarbon receptor (AHR) is an environment-sensing transcription factor that contributes to vascular development, and has been implicated in coronary artery disease risk. We hypothesized that AHR can affect atherosclerosis by regulating phenotypic modulation of SMC.MethodsWe combined RNA-sequencing, chromatin immunoprecipitation followed by sequencing, assay for transposase-accessible chromatin using sequencing, and in vitro assays in human coronary artery SMCs, with single-cell RNA-sequencing, histology, and RNAscope in an SMC-specific lineage-tracing Ahr knockout mouse model of atherosclerosis to better understand the role of AHR in vascular disease.ResultsGenomic studies coupled with functional assays in cultured human coronary artery SMCs revealed that AHR modulates the human coronary artery SMC phenotype and suppresses ossification in these cells. Lineage-tracing and activity-tracing studies in the mouse aortic sinus showed that the Ahr pathway is active in modulated SMCs in the atherosclerotic lesion cap. Furthermore, single-cell RNA-sequencing studies of the SMC-specific Ahr knockout mice showed a significant increase in the proportion of modulated SMCs expressing chondrocyte markers such as Col2a1 and Alpl, which localized to the lesion neointima. These cells, which we term "chondromyocytes," were also identified in the neointima of human coronary arteries. In histological analyses, these changes manifested as larger lesion size, increased lineage-traced SMC participation in the lesion, decreased lineage-traced SMCs in the lesion cap, and increased alkaline phosphatase activity in lesions in the Ahr knockout in comparison with wild-type mice. We propose that AHR is likely protective based on these data and inference from human genetic analyses.ConclusionsOverall, we conclude that AHR promotes the maintenance of lesion cap integrity and diminishes the disease-related SMC-to-chondromyocyte transition in atherosclerotic tissues.
| S-EPMC8066499 | biostudies-literature
Project description:Genome-wide association studies (GWAS) for coronary artery disease (CAD, also termed coronary heart disease, CHD) have discovered and validated 48 loci genome-wide and recent 1000-Genomes based meta-analyses have discovered additional 8 loci with significant association, however, true follow-up studies on the mechanisms of association are still scarce. Here we analyze the relationship of two transcription factors, TCF21, one of the lead GWAS candidate genes for coronary artery disease and AHR, aryl hydrocarbon receptor, which previously was not implicated as fundamental for the atherosclerotic process. We show that both the predicted and in-vivo ChIP-Seq binding sites for TCF and AHR colocalize in the human genome with over 400 predicted sites and 119 ChIP-Seq sites directly overlapping. TCF and AHR-ARNT predicted binding sites longitudinal phasing was observed near the transcription start sites, outlining the position of +1 nucleosome. AHR-ARNT matrix was highly enriched in both TCF21 ChIP-Seq peaks and ATAC-Seq open chromatin regions in human coronary artery smooth muscle cells (HCASMC), implicating the role of AHR in this important cell type for vascular biology. Co-expression modules of TCF21 and AHR showed high degree of connectivity. Separation of rotationally phased and unphased predicted binding sites for TCF and AHR resolved the roles of direct and indirect TCF-AHR interactions, and implicated as highly-modulated various inflammatory, interleukin and cytokine related processes, while ChIP-Seq co-localization of TCF21 and AHR/ARNT emphasized the role of calcium related processes. We performed TCF21 overexpression analysis in human coronary artery smooth muscle cells (HCASMC) and obtained GO ontologies that recapitulate in vivo pathophysiology of the atherosclerotic vessel wall, and a set of chronic inflammatory ontologies was established with the colocalization of TCF21 and AHR ChIP-Seq sites as well as with the binomial testing of GWAS SNP overrepresentation. We experimentally confirmed that TCF21 binds to and regulates AHR gene expression in HCASMC, as well as to elements near AHR downstream genes, such as CYP1A1, using reporter assays. The functional relevance of AHR pathway in HCASMC is confirmed using AHR ligands TCDD and oxidized LDL. Finally, we show that AHR is elevated in atherosclerotic arteries using laser capture microdissection in mice in vivo and in human ex vivo. In conclusion, we extend GWAS results to functional assays and show that TCF21 and AHR functional connectivity provides a novel mechanism for diseased coronary vessel wall biology.
2017-04-12 | GSE85565 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE15857: The Aryl Hydrocarbon Receptor Regulates Tissue-Specific Dioxin-Dependent and Dioxin-Independent Gene Batteries: Kidney GSE15858: The Aryl Hydrocarbon Receptor Regulates Tissue-Specific Dioxin-Dependent and Dioxin-Independent Gene Batteries: Liver Refer to individual Series
2010-05-05 | E-GEOD-15859 | biostudies-arrayexpress
Project description:Macrophage heterogeneity within atherosclerotic plaques was explored with intravital imaging, flow cytometry, and RNA sequencing. 4 populations of cells were found with varying expression profiles and functions relevant to atherosclerosis and inflammation.
2019-09-24 | GSE137819 | GEO
Project description:Paired samples from human femoral artery lesions were obtained during intravascular surgery exploiting Silverhawk device Microarrays were used to identify genes differentially regulated in human femoral artery atherosclerotic and corresponding restenotic plaques
2014-12-01 | GSE53274 | GEO
Project description:Study of the effect of low-density lipoprotein (LDL)-lowering therapies on the heterogeneous population of proliferating smooth muscle cells (SMCs) derived from atherosclerotic plaques in an atherosclerotic mouse model by inducing hypercholesterolemia followed by high or low fat diet.
2023-12-08 | E-MTAB-12019 | biostudies-arrayexpress
Project description:VAF347 is a low molecular weight compound which inhibits allergic lung inflammation in vivo. This effect is likely due to a block of dendritic cell (DC) function to generate pro-inflammatory T-helper (Th) cells since VAF347 inhibits IL-6, CD86 and HLA-DR expression by human monocyte derived DC, three relevant molecules for Th-cell generation. Here we demonstrate that VAF347 interacts with the aryl hydrocarbon receptor (AhR) protein resulting in activation of the AhR signaling pathway. Functional AhR is responsible for the biological activity of VAF347 since, i) other AhR agonists display an identical activity profile in vitro, ii) gene silencing of wild type AhR expression or forced over-expression of a trans-dominant negative AhR ablates VAF347 activity to inhibit cytokine induced IL-6 expression in a human monocytic cell line and iii) AhR deficient mice are resistant to the compound’s ability to block allergic lung inflammation in vivo. These data identify the AhR protein as key molecular target of VAF347 and its essential role for mediating the anti-inflammatory effects of the compound in vitro and in vivo. Keywords: effect of compound
2008-02-12 | GSE10463 | GEO
Project description:Acinetobacter baumannii is a highly pathogenic and multidrug-resistant Gram-negative bacterium that causes severe nosocomial infections. To better understand the mechanism of pathogenesis, we compare the proteomes of uninfected and infected human cells, revealing that transcription factor FOS is the host protein most strongly induced by A. baumannii infection. Pharmacological inhibition of FOS reduces the cytotoxicity of A. baumannii in cell-based models, and similar results are also observed in a mouse infection model. A. baumannii outer membrane vesicles (OMVs) are shown to activate the aryl hydrocarbon receptor (AHR) of host cells by inducing the host enzyme tryptophan-2,3-dioxygenase (TDO), producing the ligand kynurenine, which binds AHR. Following ligand binding, AHR is a direct transcriptional activator of the FOS gene. Our results suggest that bacterial infection interacts with host tryptophan metabolism and the transcription factor FOS.
2024-08-05 | PXD053768 | Pride
Project description:Osteoarthritis (OA) is the most prevalent chronic joint disease that affects a majority of the elderly. Chondrogenic progenitor cells (CPCs) reside in late stage OA cartilage tissue, producing a fibrocartilagenous extra-cellular matrix and can be manipulated in-vitro, to deposit proteins of healthy articular cartilage. CPCs are under control of SOX9 and RUNX2 and in order to enhance their chondrogenic potential, we found that RUNX2 plays a pivotal role in chondrogenesis. In another approach, CPCs carrying a knockout of RAB5C, a protein involved in endosomal trafficking, demonstrated elevated expression of various chondrogenic markers including the SOX trio and displayed an increased COL2 deposition, whereas no changes of COL1 deposition was observed. We report RAB5C as an attractive target for future therapeutic approaches to increase the COL2 content in the diseased joint.
2021-09-09 | PXD021785 | Pride