Integrated Multi-Omics Profiling Reveals Neutrophil Extracellular Traps Promote Aortic Dissection
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE254132 | GEO | 2024/11/01
REPOSITORIES: GEO
Similar Datasets
Project description:Aortic dissection (AD) is a major cause of acute aortic syndrome with high mortality due to the destruction of aortic walls. Although recent studies indicate the critical role of inflammation in the disease mechanism of AD, it is unclear how inflammatory response is initiated. Here, we demonstrate that myocardin-related transcription factor A (MRTF-A), a signal transducer of humoral and mechanical stress, plays an important role in pathogenesis of AD in a mouse model. A mouse model of AD was created by continuous infusion of angiotensin II (AngII) that caused dilation of thoracic aorta in 1 day and AD in 4 days. Systemic deletion of Mrtfa gene resulted in a marked suppression of AD development. Transcriptome and gene annotation enrichment analyses revealed that AngII infusion for 1 day caused pro-inflammatory and pro-apoptotic responses before AD development, which were suppressed by Mrtfa deletion. AngII infusion for 1 day induced pro-inflammatory response, as demonstrated by expressions of Il6, Tnf , and Ccl2, and apoptosis of aortic wall cells, as detected by TUNEL staining, in an MRTF-A-dependent manner. Furthermore, pharmacological inhibition of MRTF-A by CCG-203971 during AngII infusion prevented AD development, indicating that acute suppression of MRTF-A is effective in preventing the aortic wall destruction. These results indicate that MRTF-A transduces the stress of AngII challenge to the pro-inflammatory and pro-apoptotic responses, ultimately leading to AD development. Intervening this pathway may represent a potential therapeutic strategy.
2020-04-01 | GSE138484 | GEO
Project description:Aneurysmatic and dissection cells show a specific alteration of gene expression, which allow a disease specific distinction. We used microarrays to analyse the cellular gene expression of controls, thoracic aortic aneurysm, and aortic dissection.
2022-12-02 | GSE219204 | GEO
Project description:Background—Aortic dissection (AD) is a life-threatening medical emergency caused by the abrupt destruction of the intimomedial layer of the aortic walls. As previous studies have reported the involvement of proinflammatory cytokine IL-6 in AD pathogenesis, we investigated the role of Stat3 signaling, a downstream pathway of IL-6 in macrophages in pathogenesis of AD. Methods and Results—We characterized the pathological and molecular events triggered by aortic stress, which can lead to AD. Aortic stress on the suprarenal aorta due to infrarenal aorta stiffening and angiotensin II infusion for 1 week caused focal medial rupture at the branching point of the celiac trunk and superior mesenteric artery. This focal medial rupture in 6 weeks in wild type (WT) mice but progressed to AD in mice with macrophage-specific deletion of Socs3 gene (mSocs3-KO). mSocs3-KO mice showed premature activation of cell proliferation, an inflammatory response, and skewed differentiation of macrophages toward the tissue-destructive phenotype. Concomitantly, they showed aberrant phenotypic modulation of SMCs and TGFβ signaling, which are likely to participate in tissue repair. Human AD samples revealed STAT3 activation in adventitial macrophages adjacent to the site of tissue destruction. Conclusions—These findings suggest that AD development is preceded by focal medial rupture, in which macrophage Socs3 maintains proper inflammatory response and differentiation of SMCs, thus promoting fibrotic healing to prevent tissue destruction and AD development. Understanding the sequence of the pathological and molecular events preceding AD development will help predict and prevent AD development and progression.
2017-11-30 | GSE107479 | GEO
Project description:Rationale— Aortic dissection (AD) is a fatal disease that occurs suddenly without preceding clinical signs or symptoms. It is desirable to prevent AD before the onset. Although high salt intake is an established risk factor for cardiovascular diseases, the relationship between high salt intake and AD has not been clarified. Although recent studies have shown that high salt intake promotes interleukin (IL)-17-dependent inflammation, it is unknown whether this mechanism is involved in the pathogenesis of AD. Objective— The purpose of this study was to investigate the effect of high salt challenge on AD and involvement of IL-17. Methods and Results— We used a mouse AD model that was induced by continuous infusion of -aminopropionitrile and angiotensin II. High salt challenge exacerbated AD lesion length compared to the mice without high salt challenge, which was abolished in IL-17 knockout mice. Unexpectedly, deletion of IL-17 resulted in the activation of Smad pathway, induction of synthetic phenotype of smooth muscle cells, remodeling of extracellular matrix in aortic tunica media, reduced stiffness of aortic walls, and less stress-induced activation of NFkB. Conclusions— These findings establish the worsening effect of high salt intake on AD that involves IL-17 pathway through the extracellular matrix metabolism. Salt restriction may represent a low-cost and practical way to reduce AD risk.
2018-12-31 | GSE116434 | GEO
Project description:To assess the circular RNAs (circRNAs) expression profile and explore the potential functions in human thoracic aortic dissection (TAD).The differentially expressed circRNAs profiles of the aortic segments between human type A TAD patients (n=3) and age-matched normal donors (NA; n=3) were analyzed using the Arraystar human circRNAs microarray. Quantitative real-time PCR was used to validate the expression pattern of circRNAs, parental genes, and hsa-miR-320a; Western blotting confirmed MMP9 expression with additional samples. Bioinformatic tools including network analysis, Gene ontology, and KEGG pathway analysis were utilized.
2020-04-12 | GSE97745 | GEO
Project description:To identify the m6A methylome in the aorta of patients with acute aortic dissection. MeRIP-seq and RNA-seq experiments of aortic media tissue samples obtained from AD patients and controls were conducted. Compared with control group, the upmethylated coding genes of AD were primarily enriched in the processes associated with extracellular fibril organization, while the genes with downmethylation were enriched in the processes associated with cell death regulation. Furthermore, many differentially methylated m6A sites (DMMSs) coding proteins were mainly annotated during the extracellular matrix and inflammatory responses.
2020-03-17 | GSE147026 | GEO
Project description:Objective—We aimed to elucidate how the inflammatory response is involved in AD progression and the associated tissue destruction, focusing on the role of Jak/Stat signaling in smooth muscle cells (SMCs). Background—Aortic dissection (AD) is caused by disruption of the intima-media complex and tearing of the medial layer of the aorta. AD is life-threatening due to progressive destruction of the aorta, resulting in critical damage to organs. Recent studies reveal that the inflammatory response, including Jak/Stat signaling, is important in AD pathogenesis. However, it remains unclear how Jak/Stat signaling is involved in the tissue destruction in AD. Methods—Immunohistochemical analysis of human AD tissue revealed activation of signal transducer and activator of transcription 3 (Stat3) in medial SMCs. Stat3 activation was recapitulated in a mouse model of AD induced via β-aminopropionitrile and angiotensin II infusion. We also created a knockout mouse strain (smSocs3-KO) by deleting Socs3, a negative regulator of Jak/Stat signaling, specifically in mouse SMCs. Results—Compared to wild-type mice, smSocs3-KO mice developed a less severe AD phenotype that was associated with proinflammatory response at baseline, increased fibroblast and collagen deposition, and reinforced aortic tensile strength. Cell culture experiments revealed that Stat3 activation in SMCs caused secretion of factors that can stimulate fibroblast growth. Conclusions—Our present findings suggested that, although an acute inflammatory response is detrimental in AD, chronic activation of the SMC-mediated proinflammatory response was protective against aortic destruction in AD.
2020-04-01 | GSE147078 | GEO
Project description:Background and aims: Aortic dissection (AD) is a cardiovascular emergency with degeneration of the aortic media. Mounting evidence indicates obstructive sleep apnea (OSA) as an independent risk factor for AD development with unknown mechanisms. This study aims to establish a stable murine model of OSA-related AD (OSA-AD) and uncover the potential changes in gene transcripts in OSA-AD. Materials and methods: ApoE-/- mice were exposed to the chronic intermittent hypoxia (CIH) system combined with Ang II administration to establish the OSA-AD model. Pathological staining was performed to exhibit the physiological structure of the mouse aorta. The SBC mouse ceRNA microarray was used to identify significantly differentially expressed (DE) mRNAs, DE long-non-coding RNAs (DElncRNAs), and DE circular RNAs (DEcircRNAs) in OSA-AD tissues. Subsequently, bioinformatics analysis, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genome (KEGG), and protein–protein interaction (PPI) analyses, was performed to evaluate the function of the significantly differentially expressed transcripts (DETs). The hub genes were confirmed using quantitative real-time polymerase chain reaction (qRT-PCR). Results: ApoE-/- mice exposed to CIH and Ang II showed a high ratio of aortic accident (73.33%) and significant aortic diameter dilatation (1.96 ± 0.175 mm). A total of 1,742 mRNAs, 2,625 lncRNAs, and 537 circRNAs were identified as DETs (LogFC ≥ 1.5 or ≤ –1.5, P < 0.05). GO and KEGG analyses demonstrated that the differentially expressed mRNAs (DEmRNAs) were most enriched in cell proliferation, migration, apoptosis, inflammation, and hypoxia-related terms, which are closely related to aortic structural homeostasis. The PPI network contained 609 nodes and 934 connections, the hub genes were highlighted with the CytoHubba plugin and confirmed by qRT-PCR in AD tissues. KEGG pathway analysis revealed that the cis-regulated genes of DElncRNAs and circRNAs-host genes were enriched in aortic structural homeostasis-related pathways. Conclusion: Our findings help establish a de novo OSA-AD animal model using ApoE-/- mice. Many DEmRNAs, DElncRNAs, and DEcircRNAs were screened for the first time in OSA-AD tissues. Our findings provide useful bioinformatics data for understanding the molecular mechanism of OSA-AD and developing potential therapeutic strategies for OSA-AD.
2022-11-16 | GSE215935 | GEO
Project description:Aortic dissection (AD) is a cardiovascular emergency resulted from blood flows into vessel wall, with high mortality in early stage. Due to the vital pathological mechanism for AD occurrence has not been clarified, and no effective ways to prevent and diagnose AD’s process. In this study, we determine the lncRNA expression profile in aortic dissection group and control group. The key lncRNAs were screen out by using microarray analysis in defferent group.
2021-09-15 | GSE183997 | GEO
Project description:To identify the m6A methylome in the aorta of patients with acute aortic dissection. MeRIP-seq and RNA-seq experiments of aortic media tissue samples obtained from AD patients and controls were conducted. Compared with control group, the upmethylated coding genes of AD were primarily enriched in the processes associated with extracellular fibril organization, while the genes with downmethylation were enriched in the processes associated with cell death regulation. Furthermore, many differentially methylated m6A sites (DMMSs) coding proteins were mainly annotated during the extracellular matrix and inflammatory responses.
2020-03-17 | GSE147027 | GEO