Gene Expression Signature in Peripheral Blood Detects Thoracic Aortic Aneurysm
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE9106 | GEO | 2008/01/29
SECONDARY ACCESSION(S): PRJNA102635
REPOSITORIES: GEO
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Project description:Current understanding on the pathogenesis of thoracic aortic aneurysms (TAAs) in Marfan Syndrome (MFS) mainly focuses on vascular smooth muscle cell (VSMC) pathologies. Whether immune cell-mediated inflammation drives the progression of TAAs is still elusive. Using single-cell RNA sequencing, a subset of macrophages highly expressing CX3CR1 and mainly locating in the aortic intima was identified in aortic root and ascending aortas from Fbn1C1041G/+ mice, and further validated in MFS patients. Specific elimination of CX3CR1+ macrophages by diphtheria toxin in Cx3cr1-CreERT2iDTRF/+Fbn1C1041G/+ mice efficiently ameliorated TAA progression, suggesting their pathogenic action. Using monoclonal antibodies Adalimumab and Teprotumumab to respectively neutralize the proinflammatory cytokines TNFalpha and IGF1 produced by CX3CR1+ macrophages from MFS patients substantially suppressed CX3CR1+ macrophage-mediated inflammation in MFS patient-specific induced pluripotent stem cell (iPSC)-derived VSMCs. Furthermore, bone marrow transplantation and parabiosis using Cx3cr1GFP/+ mice revealed the intimal CX3CR1+ macrophages derived from circulating monocytes. Administration of CCR2 antagonist RS504393 to inhibit monocyte infiltration significantly reduced intimal CX3CR1+ macrophages and subsequently alleviated TAA development in Fbn1C1041G/+ mice. In conclusion, intimal CX3CR1+ macrophages mediated TAA formation through paracrinally causing VSMC inflammation. Targeting intimal CX3CR1+ macrophages would be a promising anti-inflammatory strategy in TAA therapy for MFS.
2024-12-10 | GSE249352 | GEO
Project description:In this study, we identified various cell clusters in human normal/sporadic TAA ascending aorta samples by single-cell RNA sequencing (scRNA-seq), and discovered the senescent vascular smooth muscle cells (VSMCs) significantly increased in TAA samples. Then we explored the molecular basis of TAA progression, and recognized the key regulators and pathways involved in the TAA progression regulation.
2023-12-01 | GSE143921 | GEO
Project description:As the EU IP @neurIST Project aims at integrating biomedical informatics technologies in the assessment of rupture risks and treatments of cerebral aneurysms in humans. Genetic involvement in the disease is known, mRNA biomarkers will be searched as possible risk factors in easy to assess PBMCs (peripheral blood cells). The aim of this pilot study is specifically to check the clinical samples going from the patientï¾s bed side to the genomic analysis platform. Briefly, we hybridized biotin labelled cRNA from 2 controls (C1, C2), 1 patient bearing an intracranial aneurysm (I) and 1 patients bearing an intracranial aneurysm and subarachnoid haemorrhage (S). For each sample, one technical replicate was performed. Thus a total of 8 arrays was used.
2010-12-01 | E-TABM-421 | biostudies-arrayexpress
Project description:BACKGROUND: Thoracic aortic aneurysm (TAA) is usually asymptomatic and associated with high mortality. Adverse clinical outcome of TAA is preventable by elective surgical repair; however, identifying at-risk individuals is difficult. We hypothesized that gene expression patterns in peripheral blood cells may correlate with TAA disease status. Our goal was to identify a distinct gene expression signature in peripheral blood that may identify individuals at risk for TAA. METHODS AND FINDINGS: Whole genome gene expression profiles from 94 peripheral blood samples (collected from 58 individuals with TAA and 36 controls) were analyzed. Significance Analysis of Microarray (SAM) identified potential signature genes characterizing TAA vs. normal, ascending vs. descending TAA, and sporadic vs. familial TAA. Using a training set containing 36 TAA patients and 25 controls, a 41-gene classification model was constructed for detecting TAA status and an overall accuracy of 78+/-6% was achieved. Testing this classifier on an independent validation set containing 22 TAA samples and 11 controls yielded an overall classification accuracy of 78%. These 41 classifier genes were further validated by TaqMan real-time PCR assays. Classification based on the TaqMan data replicated the microarray results and achieved 80% classification accuracy on the testing set. CONCLUSIONS: This study identified informative gene expression signatures in peripheral blood cells that can characterize TAA status and subtypes of TAA. Moreover, a 41-gene classifier based on expression signature can identify TAA patients with high accuracy. The transcriptional programs in peripheral blood leading to the identification of these markers also provide insights into the mechanism of development of aortic aneurysms and highlight potential targets for therapeutic intervention. The classifier genes identified in this study, and validated by TaqMan real-time PCR, define a set of promising potential diagnostic markers, setting the stage for a blood-based gene expression test to facilitate early detection of TAA.
| S-EPMC2002514 | biostudies-literature
Project description:Based on sequencing technology to evaluate the differential lncRNA and mRNA expression of intracranial aneurysms. Provide ideas for the study of epigenetic regulation of intracranial aneurysms
2020-09-26 | GSE158558 | GEO
Project description:Inadequate adaption to mechanical forces, including an elevated blood pressure, contributes to the development of arterial aneurysms. Recent studies have pointed to a mechano-protective role of YAP and TAZ in vascular smooth muscle cells (SMCs). Here, we created vascular SMC-specific knockouts (KOs) of YAP and TAZ using integrin-alpha8-Cre mice (i8-YT-KO). I8-YT-KO mice spontaneously developed aneurysms in the abdominal aorta within two weeks of knockout induction. Loss of YAP expression was also observed in human aortic aneurysms. I8-YT-KO mice developed vascular lesions in other arteries at later times, but the gastrointestinal tract was spared. Aneurysms were characterized by elastin disarray, SMC apoptosis, and accumulation of proteoglycans and inflammatory cells, including macrophages and neutrophils. RNA-sequencing, proteomics, and myography demonstrated decreased contractile differentiation of SMCs and impaired vascular contractility. This associated with partial loss of vascular myocardin expression, reduced blood pressure, and edema. Mediators in the cGAS-STING pathway, which sparks inflammation in response to double-stranded DNA, were increased in aortic lysates. A sizeable increase of the transcription factor Sox9, along with several direct target genes, including aggrecan (Acan), contributed to proteoglycan accumulation. This was the earliest detectable change, occurring three days after knockout induction, and before the pro-inflammatory transition. In conclusion, Itga8-Cre deletion of YAP and TAZ represents a rapid and spontaneous aneurysm model that re-capitulates features of human abdominal aortic aneurysms.
2023-03-10 | MSV000091464 | MassIVE
Project description:Descending thoracic aortic aneurysms and dissections can go undetected until severe and catastrophic, and few clinical indices exist to screen for aneurysms or predict their risk of dissection or rupture. This study generated a plasma proteomic dataset from 150 patients with descending thoracic aortic disease and 52 controls to identify proteomic signatures capable of differentiating descending thoracic aortic disease from non-disease controls, as well as between cases with aneurysm versus descending ‘type B’ dissection. Of the 1,468 peptides and 195 proteins quantified across all samples, 853 peptides and 99 proteins were quantitatively different between disease and control patients (BH adjusted p-value < 0.01 from t-tests). Supervised machine learning (ML) methods were used to classify disease from control and aneurysm from descending dissection cases. The highest precision-recall area under the curve (PR AUC) was achieved on the held-out test set using significantly different proteins between disease and control patients (PR AUC 0.99), followed by input of significant peptides (PR AUC 0.96). Despite no statistically significant proteins between aneurysm and dissection cases, use of all proteins was able to modestly classify between the two disease states (PR AUC 0.77). To overcome correlation in the proteins and enable biological pathway analysis, a disease versus control classifier was optimized using only seven unique protein clusters, which achieved comparable performance to models trained on all/significant proteins (accuracy 0.88, F1-score 0.78, PR AUC 0.90). Model interpretation with permutation importance revealed that proteins in the most important clusters for differentiating disease and control function in coagulation, protein-lipid complex remodeling, and acute inflammatory response.
2024-06-16 | PXD041337 | Pride
Project description:Background and Purpose—Analyzing genes involved in development and rupture of intracranial aneurysms can enhance knowledge about the pathogenesis of aneurysms, and identify new treatment strategies. We compared gene expression between ruptured and unruptured aneurysms and control intracranial arteries. Methods—We determined expression levels with RNA sequencing. Applying a multivariate negative binomial model, we identified genes that were differentially expressed between 44 aneurysms and 16 control arteries, and between 22 ruptured and 21 unruptured aneurysms. The differential expression of 8 relevant and highly significant genes was validated using digital polymerase chain reaction. Pathway analysis was used to identify enriched pathways. We also analyzed genes with an extreme pattern of differential expression: only expressed in 1 condition without any expression in the other. Results—We found 229 differentially expressed genes in aneurysms versus controls and 1489 in ruptured versus unruptured aneurysms. The differential expression of all 8 genes selected for digital polymerase chain reaction validation was confirmed. Extracellular matrix pathways were enriched in aneurysms versus controls, whereas pathways involved in immune response and the lysosome pathway were enriched in ruptured versus unruptured aneurysms. Immunoglobulin genes were expressed in aneurysms, but showed no expression in controls. Conclusions—For rupture of intracranial aneurysms, we identified the lysosome pathway as a new pathway and found further evidence for the role of the immune response. Our results also point toward a role for immunoglobulins in the pathogenesis of aneurysms. Immune-modifying drugs are, therefore, interesting candidate treatment strategies in the prevention of aneurysm development and rupture.
2018-11-26 | GSE122897 | GEO
Project description:Mutations in the Fbn1 gene cause Marfan Syndrome (MFS) and are associated with excessive transforming growth factor beta (TGF-β) signalling activation, which contributes to extracellular matrix (ECM) homeostasis disruption, thoracic aortic aneurysm (TAA) and dissection development. In this study, we aimed to explore the underlying events contributing to ECM metabolism imbalance and TAA and dissection formation in MFS. We performed sequencing analysis and investigated differentially expressed genes as well as cellular communication using CellChat. Fourteen ECM-related differentially expressed genes (DEGs) were identified. Among the 14 genes, secreted phosphoprotein 1 (Spp1) was involved in multiple pathological processes. We then stimulated primary mouse perivascular fibroblasts and aortic SMCs with recombinant Spp1 and recorded increased collagen expression in fibroblasts and decreased expression of Acta2 and Tagln in SMCs. We also investigated SPP1 levels in healthy controls and patients with TAA and found that elevated SPP1 levels were associated with an increased risk of TAA. Our results have indicated that Spp1 regulates ECM changes in fibroblasts and SMCs contractility during TAA. We believe that our study makes a significant contribution to the literature because our results suggest that Spp1 may serve as a potential target for TAA treatment.
2024-12-12 | GSE190720 | GEO
Project description:Analysis of differential gene expression for rutured vs stable abdominal aortic aneurysms (AAA) and for intermediate size (≤55mm) vs large (>70mm) AAA.
2018-02-27 | GSE98278 | GEO