MiRNA expression profiles of aneurysmal tissues
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE110527 | GEO | 2019/09/18
REPOSITORIES: GEO
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Project description:In current models of ascending aortic disease, mural cells undergo phenotypic changes that promote extracellular matrix destruction and structural weakening. To explore the intersection of this biology with quantitative trait GWAS loci we analyzed the genetic features of thoracic aortic aneurysm tissue. Single nuclear RNA sequencing was performed on 13 samples from human donors, 6 with thoracic aortic aneurysm and 7 without aneurysm. Individual transcriptomes were then clustered based on transcriptional profiles. Clusters were used for between-disease differential gene expression analyses, subcluster analysis, and analyzed for intersection with genetic aortic trait data. In total, we sequenced 71,689 nuclei from human thoracic aortas without aneurysm, and with sporadic aneurysm. We identified 14 clusters, aligning with 11 cell types, predominantly VSMCs, consistent with existing histologic data, but contrary to the majority of human aortic single cell studies to-date. With unbiased methodology, we found 7 VSMC and 6 fibroblast subclusters. Differentially expressed genes (DEGs) analysis revealed a VSMC group accounting for the majority of differential gene expression. Fibroblast populations in aneurysm exhibit distinct behavior with almost complete disappearance of quiescent fibroblasts. DEGs were used to prioritize genes at aortic diameter and distensibility GWAS loci highlighting the genes JUN, LTBP4, and IL34 in fibroblasts, ENTPD1, PDLIM5, ACTN4, and GLRX in VSMCs, as well as LRP1 in macrophage populations. In conclusion, using nuclear RNA sequencing we describe the cellular diversity of healthy and aneurysmal human ascending aorta. Sporadic aortic aneurysm is characterized by differential gene expression within known cellular classes rather than by the appearance of novel cellular forms. Single nuclear RNA sequencing of aortic tissue can be used to prioritize genes at aortic trait loci.
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Project description:Bicuspid aortic valve (BAV) is the most common congenital cardiovascular disease in general population and is frequently associated with the development of thoracic aortic aneurysm (TAA). There is no effective strategy to intervene with TAA progression due to an incomplete understanding of the pathogenesis. In this study, protein analyses of human aortic tissues showed the insufficient expression of NOTCH1 and impaired mitochondrial dynamics in BAV-TAA. To verify it, we constructed aorta-on-a-chip to replicate the rhythmic tensile on human aorta, on which human aortic smooth muscle cells (HAoSMCs) endured a microenvironment of biomimetic strain unattainable in animal models. HAoSMCs with NOTCH1-knockdown exhibited reduced contractile phenotype and were accompanied by attenuated mitochondrial fusion. Furthermore, we identified that mitochondrial fusion activators (leflunomide and teriflunomide) or mitochondrial fission inhibitor (Mdivi-1) rescued the mitochondrial dysfunction in HAoSMCs from BAV-TAA patients. These findings suggest that impaired mitochondrial dynamics could be a potential therapeutic target for BAV-TAA.
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Project description:Using Cdh5-Cre and Sm22-Cre transgenes to characterize the impact of disruption of the angiotensin II type 1a receptor (AT1ar) in vascular endothelial and smooth muscle cells, respectively, of wild type (WT) mice compared to fibrillin-1 hypomorphic mice (Fbn1mgR/mgR mice) that replicate early onset progressively severe Marfan syndrome (MFS) with dissecting thoracic aortic aneurysm (TAA).
2018-01-30 | GSE109797 | GEO
Project description:To improve our limited understanding of the pathogenesis of thoracic aortic aneurysm (TAA) leading to acute aortic dissection, we used single-cell RNA sequencing to profile disease-relevant transcriptomic changes of aortic cell populations in a well-characterized mouse model of the most commonly diagnosed form of Marfan syndrome (MFS). As result,MFSmod were identified only in the aorta of Fbn1mgR/mgR mice. In situ hybridizations of diagnostic transcripts located MFSmod cells to the intima of Fbn1mgR/mgR aortas. Consistent with angiotensin II type I receptor (At1r) contribution to TAA development, MFSmod cells were absent in the aorta of Fbn1mgR/mgR mice treated with the At1r antagonist losartan. Altogether, our findings indicate that a discrete dynamic alteration of aortic cell identity is associated with dissecting TAA in MFS mice and increased risk of aortic dissection in MFS patients.
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Project description:We analyzed differentially expressed genes in smooth muscle cells derived from the thoracic aorta of Marfan Syndrome (MFS) patients and control subjects to identify cell biological mechanisms contributing to thoracic aoritc aneurysm (TAA) development and rupture. These mechanisms were used to identify a potential drug treatment to mitigate TAA progression. We analyzed differentially expressed genes in whole aorta of P16 MFS mice vs WT mice to identify cell biological mechanisms contributing to thoracic aoritc aneurysm (TAA) development and rupture. These mechanisms were used to identify baclofen as a potential drug treatment to mitigate TAA progression. The effect of baclofen on gene expression in WT and MFS was documented in P60 mice that received treatment since P16.
2019-11-18 | GSE128101 | GEO
Project description:Thoracic aortic aneurysms have a higher prevalence in male patients compared to female patients. Marfan syndrome causes a hereditary form of TAA with dilation of the aortic root. Male patients with Marfan syndrome are more likely than women to have aortic dilation and dissection and mouse models of Marfan syndrome demonstrate larger aortic roots in males compared to females even after adjustment for body size. Similar sex disparities are present in patients and models of abdominal aortic aneurysms where estrogen has been demonstrated to attenuate aneurysm formation perhaps through anti-inflammatory mechanisms. In this study we demonstrate the effects of estrogen on aortic dilation and rupture in a Marfan mouse model and we investigate if these effects operate through suppression of complement components of the immune system.
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Project description:In the present study, we evaluated miRNA expression profiles of 32 patient aortic aneurysm tissue and plasma samples using Illumina next-generation sequencing platform. A total of 20 miRNA were differentially expressed in tissues, 17 miRNAs - in plasma samples. Differentially expressed miRNAs determined in the present study could be applied for thoracic ascending aneurysm diagnosis.
2020-04-14 | GSE122266 | GEO
Project description:Thoracic aortic aneurysms (TAA) in Marfan syndrome, caused by fibrillin-1 mutations, are characterized by elevated cytokines and fragmentated elastic laminae in the aortic wall. This study explored whether and how specific fibrillin-1-regulated miRNAs mediate inflammatory cytokine expression and elastic laminae degradation in TAA. miRNA expression profiling at early and late TAA stages using a severe Marfan mouse model (Fbn1mgR/mgR) revealed a spectrum of differentially regulated miRNAs. Bioinformatic analyses predicted the involvement of these miRNAs in inflammatory and extracellular matrix related pathways. Complementing mRNA microarray demonstrated the upregulation of multiple pro-inflammatory cytokines and matrix metalloproteases. Correlation analyses between the altered miRNAs and mRNAs present miR-122, the most downregulated miRNAs in the TAA tissue of Fbn1mgR/mgR, to be a core regulatory miRNA to pro-inflammatory cytokines, Ccl2 and Il1b, which were upregulated in the TAA tissues. At 10 weeks, the number of differentially regulated miRNAs (>2-fold) increased to 129 with 5 down- and 124 upregulated miRNAs
2022-05-21 | GSE199283 | GEO
Project description:Objective - Thoracic aortic aneurysm (TAA), a degenerative disease of the aortic wall, is accompanied by changes in the structure and composition of the aortic extracellular matrix (ECM). The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family has recently been implicated in TAA formation. This study aimed to investigate the contribution of ADAMTS-5 to TAA development. Approach and Results - A model of aortic dilatation by angiotensin II (AngII) infusion was adopted in mice lacking the catalytic domain of ADAMTS-5 (Adamts5Δcat). Adamts5Δcat mice showed an attenuated rise in blood pressure whilst displaying increased dilatation of the ascending aorta. Interestingly, a comparison of the aortic ECM from AngII-treated wildtype and Adamts5Δcat mice revealed versican as the most up-regulated ECM protein in Adamts5Δcat mice. This was accompanied by a marked reduction of ADAMTS-specific versican cleavage products (versikine) and a decrease of low-density lipoprotein-related protein 1 (LRP1). Silencing LRP1 expression in human aortic smooth muscle cells reduced the expression of ADAMTS5, attenuated the generation of versikine but increased soluble ADAMTS-1. A similar increase in ADAMTS-1 was observed in aortas of AngII-treated Adamts5Δcat mice, but was not sufficient to maintain versican processing and prevent aortic dilatation. Conclusions - Our results support the emerging role of ADAMTS proteases in TAA. ADAMTS-5 rather than ADAMTS-1 is the key protease for versican regulation in murine aortas. Further studies are needed to define the ECM substrates of the different ADAMTS proteases and their contribution to TAA formation.
2018-05-08 | PXD009410 | Pride