Transcription profiling of human atherosclerotic lesion SMC cells resistant and sensitive to TGF and Fas ligation by CH11 antibody
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Timothy McCaffrey
PROVIDER: E-GEOD-2522 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Publications
Genomic profiling of acquired resistance to apoptosis in cells derived from human atherosclerotic lesions: potential role of STATs, cyclinD1, BAD, and Bcl-XL.
Gagarin Dmitry D Yang Zhaoqing Z Butler Jason J Wimmer Monika M Du Baoheng B Cahan Patrick P McCaffrey Timothy A TA
Journal of molecular and cellular cardiology 20050901 3
Current theories suggest that atherosclerosis, plaque rupture, stroke, and restenosis after angioplasty may involve defective apoptotic mechanisms in vascular cells. Prior work has demonstrated that cells from human atherosclerotic lesions, and cells from the aorta of aged rats, exhibit functional resistance to apoptosis induced by TGF-beta and glucocorticoids. The present studies demonstrate that human lesion-derived cells (LDC) are also resistant to apoptosis induced by fas ligation compared t ...[more]
Similar Datasets
Project description:Comparison of SMC resistant and sensitive to TGF and Fas ligation by CH11 antibody Keywords: other
2005-04-13 | GSE2522 | 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:Idiopathic pulmonary fibrosis (IPF) is associated with the accumulation of collagen-secreting fibroblasts and myofibroblasts in the lung parenchyma. Many mechanisms contribute to their accumulation, including resistance to apoptosis. In previous work, we showed that exposure to the pro-inflammatory cytokines, TNF-α and IFN-γ reverses fibroblast resistance to apoptosis. The goal of this study was to investigate the underlying mechanism. Based on an initial interrogation of the transcriptomes of unstimulated and TNF-α and IFN-γ-stimulated primary lung fibroblasts and the lung fibroblast cell line, MRC5, we show here that among Fas-signaling pathway molecules, Fas expression was increased ~6-fold in an NF-κB and p38mapk-dependent fashion. Prevention of the increase in Fas expression using Fas siRNAs blocked the ability of TNF-α and IFN-γ to sensitize fibroblasts to Fas ligation induced-apoptosis; while enforced adenovirus-mediated Fas overexpression was sufficient to overcome basal resistance to Fas-induced apoptosis. Examination of lung tissues from IPF patients revealed low to absent staining of Fas in fibroblastic cells of fibroblast foci. Collectively, these findings suggest that increased expression of Fas is necessary and sufficient to overcome the resistance of lung fibroblasts to Fas-induced apoptosis. They also suggest that approaches aimed at increasing Fas expression by lung fibroblasts and myofibroblasts may be therapeutically relevant. To investigate the mechanism by which TNF-α and IFN-γ reprogram fibroblasts from resistance to sensitivity to Fas-ligation-induce apoptosis, we exposed human primary lung fibroblasts from an IPF patient (FS087) and non-disease control subject (N78) and the human fetal lung fibroblast cell lung (MRC-5) to TNF-α (10 ng/ml) and IFN-γ (50 U/ml) for 36 hr and analyzed changes in their transcriptomes using Affymetrix microarrays.
2011-01-13 | E-GEOD-26594 | biostudies-arrayexpress
Project description:Idiopathic pulmonary fibrosis (IPF) is associated with the accumulation of collagen-secreting fibroblasts and myofibroblasts in the lung parenchyma. Many mechanisms contribute to their accumulation, including resistance to apoptosis. In previous work, we showed that exposure to the pro-inflammatory cytokines, TNF-α and IFN-γ reverses fibroblast resistance to apoptosis. The goal of this study was to investigate the underlying mechanism. Based on an initial interrogation of the transcriptomes of unstimulated and TNF-α and IFN-γ-stimulated primary lung fibroblasts and the lung fibroblast cell line, MRC5, we show here that among Fas-signaling pathway molecules, Fas expression was increased ~6-fold in an NF-κB and p38mapk-dependent fashion. Prevention of the increase in Fas expression using Fas siRNAs blocked the ability of TNF-α and IFN-γ to sensitize fibroblasts to Fas ligation induced-apoptosis; while enforced adenovirus-mediated Fas overexpression was sufficient to overcome basal resistance to Fas-induced apoptosis. Examination of lung tissues from IPF patients revealed low to absent staining of Fas in fibroblastic cells of fibroblast foci. Collectively, these findings suggest that increased expression of Fas is necessary and sufficient to overcome the resistance of lung fibroblasts to Fas-induced apoptosis. They also suggest that approaches aimed at increasing Fas expression by lung fibroblasts and myofibroblasts may be therapeutically relevant.
2011-01-13 | GSE26594 | GEO
Project description:ATAC-seq in paired SMC vs. Non-SMC
| PRJNA664053 | ENA
Project description:Differential gene expression in paired SMC vs. Non-SMC
| PRJNA664763 | ENA
Project description:Poor prognosis of small cell lung cancer (SCLC) is mainly attributed to its highly metastatic capability. Here we identify the SMC and Non-SMC from Rb1L/L/Trp53 L/L mouse model through FACS with NE and mensenchymal markers. In order to identify functions of these two subpopulations during SCLC malignant progression, we compared their metastatic capability by allograft experiment. In addition, we find that the SMC is progressively transited from the Non-SCLC during mouse SCLC malignant progression. Further investigation reveals that genetic disruption of the SWI/SNF chromatin-remodeling complex, in RP model abrogates SMC phenotype maintenance and SCLC metastasis. In search of important downstream regulators, we find that TAZ, the core transcription cofactor of the Hippo pathway, is epigenetically silenced by SWI/SNF complex during this process. Collectively, our data link phenotypic transition to cancer metastasis and identify TAZ as a critical molecular switch that controls SCLC plasticity.
2022-08-24 | GSE158091 | GEO
Project description:Background/Aim: Macrophage polarization and phenotypic switching of smooth muscle cells (SMCs) are multi-faceted events dominating atherosclerosis (AS) progression. TGF-β was proved to been one of the bridge on the crosstalk between macrophage and SMC. ShenLian (SL) was extracted from a potent anti-atherosclerotic formula. However, its exact mechanism rebalancing inflammatory microenvironment of AS remain largely unknown. Within the entirety of macrophage and SMC, this study investigated the pharmacological effects of SL on stabilizing atherosclerotic plaques. Methods: The main components of SL were examined by high performance liquid chromatography. Co-culture and conditioned medium models of macrophage/SMC interactions were designed to identify the relationship between macrophage polarization and switching of SMC phenotypes. Flow cytometry, immunofluorescent staining, RT-PCR, western blotting, and ELISA were used to determine the expression of molecules relating to AS progression. An atherosclerosis animal model, established by placing a perivascular collar on the right common carotid artery in ApoE-/- mice, was used to investigate whether TGF-β is the key molecular mediator of SL in crosstalk between macrophage and SMC. Plaque size was defined by nuclear magnetic resonance imaging. Key markers related to phenotypic transformation of macrophage and SMC were determined by immunohistochemical staining. Results: Results revealed that, accompanied by rebalanced M2 macrophage polarization, SL supported SMC phenotypic transformation and functionally reconstruct the ECM of plaques specifically in macrophage-SMC co-cultural model. Molecularly, such activity of SL closely related to the activation of STAT3/SOCS3 pathway. Furthermore, in co-culture system, up-regulation of α-SMA induced by SL could neutralized by 1D11, a TGF-β neutralizing antibody, indicating that SL mediated Macrophage-SMC communication by enhancing TGF-β. In the AS model constructed by ApoE-/- mice, effects of SL on phenotypic transformation of macrophage and SMC has been well verified. Specific blocking of TGF-β largely attenuated the aforementioned effects of SL. Conclusion: Our findings highlighted that TGF-β might be the responsive factor of SL within macrophage and SMC communication. This study revealed that crosstalk between macrophage and SMC forms a holistic entirety promoting atherosclerotic plaque stability.
| S-EPMC8193129 | biostudies-literature
Project description:Poor prognosis of small cell lung cancer (SCLC) is mainly attributed to its highly metastatic capability. Here we identify the SMC and Non-SMC from Rb1L/L/Trp53 L/L mouse model through FACS with NE and mensenchymal markers. In order to identify functions of these two subpopulations during SCLC malignant progression, we compared their metastatic capability by allograft experiment. In addition, we find that the SMC is progressively transited from the Non-SCLC during mouse SCLC malignant progression. Further investigation reveals that genetic disruption of the SWI/SNF chromatin-remodeling complex, in RP model abrogates SMC phenotype maintenance and SCLC metastasis. In search of important downstream regulators, we find that TAZ, the core transcription cofactor of the Hippo pathway, is epigenetically silenced by SWI/SNF complex during this process. Collectively, our data link phenotypic transition to cancer metastasis and identify TAZ as a critical molecular switch that controls SCLC plasticity.
2022-08-24 | GSE158293 | GEO
Project description:Despite decades of research, our understanding of processes controlling the stability of late-stage atherosclerotic plaques remains poor. However, a prevailing hypothesis is that reducing inflammation may improve plaque stability. Indeed, the potent inflammatory cytokine, interleukin-1β (IL-1β), has been shown to be a key driver of atherosclerosis development. Importantly, the CANTOS Trial recently demonstrated that administration of an anti-IL-1β antibody to high-risk post-myocardial infarction (MI) patients reduced the incidence of recurrent nonfatal MI, but did not reduce the incidence of cardiovascular death or stroke. As such, although the CANTOS trial results providing exciting evidence that targeting inflammation can have clinical benefit for treating advanced atherosclerosis, extensive further investigation is needed to better understand the mechanisms by which IL-1β inhibition impacts established lesions. Therefore, we performed intervention studies on smooth muscle cell (SMC) lineage tracing mice with advanced atherosclerosis using anti-IL- 1 or IgG control antibodies. Surprisingly, we found no effect on lesion size but a profound shift in the composition of the fibrous cap characterized by reduced collagen and SMC content but an increase in macrophage number, which was primarily driven by opposite effects on the proliferation of these respective cell types. By generating SMC-specific and macrophage-selective Il1r1 KO Apoe -/- mice, we found that SMC-specific Il1r1 KO resulted in a ~60% reduction in lesion size and lesions that were nearly devoid of YFP + SMC whereas, myeloid-selective loss of IL1R1 had no effect on lesion size, or cell composition. This suggests that SMC are a primary cell type responding to IL-1β in atherosclerosis and that IL1 signaling in SMC is critical for their investment and retention within the fibrous cap. In addition, we found that inhibition of IL-1β promoted an expansion of the M2 macrophage population within the fibrous cap, and that these effects may be due in part to elevated levels of IL4. Taken together, results show that IL-1β can promote beneficial changes in late-stage murine atherosclerosis by promoting maintenance of a SMC/collagen-rich fibrous cap. Moreover, studies identify critical cell types and pathways that need to be considered when attempting to develop safer and more effective anti-inflammatory therapies for widespread treatment of atherosclerotic disease, including in moderate or low risk patients.
2018-07-12 | GSE111535 | GEO