Expression profile alteration of lncRNA and their target genes in patients with aortic dissection
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE183997 | GEO | 2021/09/15
REPOSITORIES: GEO
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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: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
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: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:Aortic dissection (AD) is a medical emergency that leads to sudden death. Effective medical therapy is not available because molecular mechanism of AD is poorly understood. We performed the transcriptome analysis in mouse AD model that was created by infusion of beta-aminopropionitrile, a collagen crosslink inhibitor, and angiotensin II. Bayesian network analysis of the transcriptome revealed several distinct gene clusters that were tightly co-regulated during AD development. Functional annotation analysis revealed that each gene cluster has distinct function, namely, cell proliferation, inflammation, cell locomotion and adhesion, and muscle differentiation. Among the gene clusters, cell proliferation cluster was the first to be activated during AD development. Cell proliferation before AD development was confirmed by immunoblotting of G1 cyclins. Immunostaining for Ki67 and cell markers revealed the proliferation of smooth muscle cells, fibroblasts, and monocytes in aortic tissue before AD development. Treatment of mice with rapamycin, an mTOR inhibitor, suppressed cell proliferative response in AD model. Rapamycin completely prevented AD when given before AD development, and effectively suppressed progression when given after AD development. Interestingly, transcriptome analysis showed that rapamycin strongly suppressed cell proliferation and muscle differentiation clusters, but its effect on inflammation cluster was modest. We concluded that mTOR constitutes an essential part of the molecular pathogenesis of AD by regulating cell proliferation, and represents a new therapeutic target.
2020-04-01 | GSE138558 | GEO
Project description:Adverse aortic remodeling increases the risk of aorta-related adverse events (AAEs) after thoracic endovascular aortic repair (TEVAR) and affects the overall prognosis of aortic dissection (AD). It is imperative to delve into the exploration of prognostic indicators to We performed single-cell transcriptomic and proteomic profiling of aortic lesions and peripheral blood samples, respectively, from patients with AD and healthy subjects. We then integrated single-cell RNA to identify phenotype-relevant subpopulations.
2024-11-01 | GSE254132 | 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:Macrophages play an important role in the progression of sporadic acute type A aortic dissection (ATAAD). The aim of this study was to characterize the cellular heterogeneity of macrophages in AD tissues by scRNA-seq. Ascending aortic wall tissue from 6 ATAAD patients and 3 heart transplant donors were assessed by scRNA-seq, then analyzed and validated by various bioinformatics algo-rithms and histopathology experiments. The results revealed the proportion of macrophages in AD tissues (24.51%) was significantly higher than that in normal tissues (13.69%). Among the 6 macro-phage subclusters, pro-inflammatory macrophages accounted for 14.96% in the AD group, and 0.18% in the normal group. Chemokine and inflammation related genes (CCL2, CCL20, S100A8, and S100A9) were expressed more intensively in macrophages in AD tissue than that in the normal tissues. Ad-ditionally, intercellular communication analysis and transcription factor analysis indicated activation of inflammation and degradation of the extracellular matrix in AD tissues. Finally, immunohisto-chemistry, immunofluorescence and western blot experiments confirmed the overexpression of macrophage marker genes (CD68 and CD163) and matrix metalloproteinases (MMP9 and MMP2) in AD tissues. Collectively, our study provides a preliminary evaluation of the role of macrophages in AD and potentially aid in the development of therapeutic options in the future.
2022-09-23 | GSE213740 | GEO
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:We report transcriptional profiles of aortic valve tissue from calcific aortic valve disease (CAVD) and normal control (non-CAVD). We collected the aortic valve tissues from five patients with CAVD who underwent aortic valve replacement due to severe aortic valve stenosis. Aortic valve samples from patients with non-calcified aortic valve resection due to heart transplantation (recipient heart) or aortic dissection were collected as the control (non-CAVD). The inclusion criteria for CAVD group were as follows: 50-75 years old; undergoing aortic valve replacement due to severe AVS with significantly valvular calcification. The inclusion criteria for non-CAVD group were as follows: non-calcified aortic valve resection due to heart transplantation (recipient heart) or aortic dissection. For each sample, total RNA was extracted, a cDNA library was generated, and an Illumina NovaSeq 6000 was used to sequence each sample. Stringtie software was used to count the fragment within each gene, and TMM algorithm was used for normalization. Differential expression analysis was performed using R package edgeR. Differentially expressed RNAs with |log2(FC)| value >1, q value [false discovery rate (FDR) adjusted P-value] <0.05, and one group’s mean fragments per kilobase of exon per million reads mapped (FPKM) >1, were assigned as differentially-expressed genes (DEGs).
2023-06-28 | GSE235995 | GEO