Unleashing the Potential: Myeloid-Specific STING Inhibition Mitigates Deep Vein Thrombosis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE247680 | GEO | 2025/07/24
REPOSITORIES: GEO
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Project description:Purpose: To explore the possible pathogenesis of venous thromboembolism from the perspective of circRNAs. Methods: The thrombus model of inferior vena cava in SD rats was established by stenosis method. Peripheral blood samples of DVT rats were collected at 1h, 6h,12h and 3d, which were sequenced with Illumina circRNAs and mRNA. The differential circRNAs and mRNA were analyzed by STEM analysis software. Clusters that can reflect the evolution of thrombus were selected for in-depth analysis, and circRNAs and mRNA were screened according to the pathway enrichment analysis of the selected clusters. Real time fluorescent quantitative PCR (qPCR) was used to verify and determine the candidate circRNAs and mRNA. The function of target circRNA was verified in DVT rats. The interacting miRNAs of circRNAs and mRNA were predicted by online database respectively. Candidate miRNAs were identified by integrating the related information of miRNAs and verified by qPCR. Results:The SD rat model of deep venous thrombosis was successfully established by the stenosis method. In model group, there were 736, 3691, 3406 and 2639 circRNAs up-regulated and 944, 327, 318 and 397 circRNAs down-regulated at 1h, 6h, 12h and 3d, respectively. Compared with Sham group, 169, 885, 298 and 500 mRNA were up-regulated and 231, 291,75 and 73 mRNA were down-regulated at 1h, 6h, 12h and 3d in model group, respectively. STEM analysis found that cluster 45 was similar to thrombus development. The pathway related to platelet function was selected in cluster 45, and 10 circrRNAs and 4 interacting mRNAs were selected for qPCR verification by combining the gene in platelet pathway and annotation gene of cluster 45 and mRNA-circRNA interaction network. According to qPCR results and whether ID is found in rat circRNA database (CIRCpedia-V2), CBT15_circR_3235 (ID in circpedia-v2: rno_CIRCpedia_1953) is determined as the target circRNA. In vivo，knockdown of rno_CIRCpedia_1953 attenuates the formation of DVT in rats. The potential target miRNAs of rno_CIRCpedia_1953 and Tuba4a were predicted by using online miRDB and miRWalk databases respectively, and rno-miR-3543, rno-miR-320-5p and rno-miR-26b-3p are preliminarily identified as potential target miRNAs that rno_CIRCpedia_1953 may combine to play the ceRNA mechanism. Conclusions: Animal model of DVT in rats was successfully established by stenosis method. High-throughput sequencing analysis of circRNAs showed that circRNAs participated in the evolution of DVT. According to STEM functional analysis of mRNA sequencing, a target circRNA rno_CIRCpedia _1953 was screened, verified and identified. rno_CIRCpedia_1953 may participate in the development of DVT by acting as miRNA molecular sponge.
2023-04-01 | GSE148331 | GEO
Project description:Purpose: To explore the possible pathogenesis of venous thromboembolism from the perspective of circRNAs. Methods: The thrombus model of inferior vena cava in SD rats was established by stenosis method. Peripheral blood samples of DVT rats were collected at 1h, 6h,12h and 3d, which were sequenced with Illumina circRNAs and mRNA. The differential circRNAs and mRNA were analyzed by STEM analysis software. Clusters that can reflect the evolution of thrombus were selected for in-depth analysis, and circRNAs and mRNA were screened according to the pathway enrichment analysis of the selected clusters. Real time fluorescent quantitative PCR (qPCR) was used to verify and determine the candidate circRNAs and mRNA. The function of target circRNA was verified in DVT rats. The interacting miRNAs of circRNAs and mRNA were predicted by online database respectively. Candidate miRNAs were identified by integrating the related information of miRNAs and verified by qPCR. Results:The SD rat model of deep venous thrombosis was successfully established by the stenosis method. In model group, there were 736, 3691, 3406 and 2639 circRNAs up-regulated and 944, 327, 318 and 397 circRNAs down-regulated at 1h, 6h, 12h and 3d, respectively. Compared with Sham group, 169, 885, 298 and 500 mRNA were up-regulated and 231, 291,75 and 73 mRNA were down-regulated at 1h, 6h, 12h and 3d in model group, respectively. STEM analysis found that cluster 45 was similar to thrombus development. The pathway related to platelet function was selected in cluster 45, and 10 circrRNAs and 4 interacting mRNAs were selected for qPCR verification by combining the gene in platelet pathway and annotation gene of cluster 45 and mRNA-circRNA interaction network. According to qPCR results and whether ID is found in rat circRNA database (CIRCpedia-V2), CBT15_circR_3235 (ID in circpedia-v2: rno_CIRCpedia_1953) is determined as the target circRNA. In vivo，knockdown of rno_CIRCpedia_1953 attenuates the formation of DVT in rats. The potential target miRNAs of rno_CIRCpedia_1953 and Tuba4a were predicted by using online miRDB and miRWalk databases respectively, and rno-miR-3543, rno-miR-320-5p and rno-miR-26b-3p are preliminarily identified as potential target miRNAs that rno_CIRCpedia_1953 may combine to play the ceRNA mechanism. Conclusions: Animal model of DVT in rats was successfully established by stenosis method. High-throughput sequencing analysis of circRNAs showed that circRNAs participated in the evolution of DVT. According to STEM functional analysis of mRNA sequencing, a target circRNA rno_CIRCpedia _1953 was screened, verified and identified. rno_CIRCpedia_1953 may participate in the development of DVT by acting as miRNA molecular sponge.
2023-04-01 | GSE148332 | GEO
Project description:Deep vein thrombosis (DVT) is a common clinical problem, but its cellular and molecular mechanisms remain incompletely understood. We performed single-cell RNA sequencing (scRNA-seq) on the vein wall of mouse inferior vena cava (IVC) ligation model of deep vein thrombosis (DVT), to analyze the transcriptomic changes in the vein wall during acute venous thrombosis.
2023-02-10 | GSE221978 | GEO
Project description:Thromboembolic diseases are commonly associated with thrombus-induced ischemia and tissue damage; identification of the location of the thrombus, or thrombus-targeting, may facilitate diagnosis and target therapy. We hypothesized that aptamers with high affinity and specificity for coagulation factor XIII (FXIII) can serve as thrombus-targeting probes. With systematic evolution of ligands by exponential enrichment technology and semi-activated FXIII (FXIII’) as the target, guanine-rich FXIII’-binding aptamers (FAs; 76 nt) were selected from a library of single-stranded DNA. Next generation sequencing identified FAs with the highest frequency; bio-layer interferometry revealed a dissociation constant (Kd) from 0.7 to 2.5 nM. Truncation with preservation of a conserved region based on entropy analysis resulted in three truncated FAs (FATs; 41-47 nt) that exhibited 4-fold signal in binding to activated vs. resting platelets, as determined by flowcytometry. In addition, FAT2 exhibited up to 4.2-fold binding of that from scrambled ssDNA to platelet/fibrin clot or whole blood clot in vitro, suggesting binding to both activated plateltes and fibrin. FAT2 also exhibited targeting effects in a microcirculatory thrombosis model in mice. Nevertheless, FATs induced no effect on blood coagulation, as determined by thromboelastometry. In conclusion, FXIII-binding aptamers are potentially amenable to thrombus targeting in theranostic application of thromboembolic diseases.
2023-12-28 | GSE163934 | GEO
Project description:Antiphospholipid syndrome (APS) is associated with arterial and venous thrombosis. The unfavorable fibrin clot phenotype, including formation of dense and poorly lysable clots, has been reported both in thrombotic APS and venous thromboembolism (VTE). The presence and amount of different proteins within a plasma clot, not only associated with the coagulation system, may influence clot properties. To our knowledge, there is a lack of data on plasma fibrin-clot bound proteins in patients with thrombotic APS or VTE. The aim of our study was to perform a quantitative proteomic analysis of fibrin clots prepared from citrated plasma from subjects with thrombotic APS and prior VTE, along with fibrin clot permeability (Ks) and clot lysis time (CLT) assessed ex vivo. We investigated 23 consecutive patients with APS, 18 with a history of first-ever VTE, and 20 age and sex matched healthy subjects. A multiple enzyme digestion filter aided sample preparation and a multienzyme digestion (MED) FASP method combined with LC-MS/MS analysis performed on a Proxeon Easy-nLC System coupled to the Q Exactive HF mass spectrometer were used. The proteomic analysis revealed that clot composition regarding 117 proteins in APS patients and 48 proteins in VTE patients was changed as compared to healthy controls, while 72 clot-bounded proteins differed between APS and VTE subjects. In healthy controls, Ks was associated with fibrinogen alpha and gamma chains (r=0.46 and r=0.46, both p<0.05, respectively) or apolipoprotein B-100 (r=-0.53, p<0.05), while CLT correlated with annexin A2 (r=-0.58, p<0.05), apolipoportein(a) (r=0.47, p<0.05), or platelet glycoprotein 4 (r=0.59, p<0.05). In VTE patients correlations of Ks with complement C1q and histone H2B, as factors closely linked with thrombosis, were observed (r=-0.52 and r=-0.47, both p<0.05, respectively). In patients with thrombotic APS all above-mentioned associations were not found. This study is the first to show that different proteins are able to influence the clot formation, structure, and properties. Since, prothrombotic conditions abolished associations observed in healthy subjects fibrin clots, differences in protein clot components might explain the links between prothrombotic fibrin clot phenotype and thromboembolic events.
2019-08-20 | PXD008434 | Pride
Project description:Atrial fibrillation (AF) is a major risk factor for cardioembolic stroke. Anticoagulant drugs are effective in preventing AF-related stroke. However, the high frequency of anticoagulant-associated major bleeding is a major concern particularly when antiplatelet treatment is simultaneously administered. Here, microarray analysis in peripheral blood cells in eight patients with AF and stroke and eight AF subjects without stroke identified a stroke related gene expression pattern. HSPA1B, which encodes for heat-shock protein 70 kDa (Hsp70), was the most differentially expressed gene. This gene was downregulated in stroke subjects, a finding confirmed further in an independent AF cohort of 200 individuals. Hsp70 knock-out (KO) mice subjected to different thrombotic challenges developed thrombosis significantly earlier than their wild-type (WT) counterparts. In WT mice, Hsp70 inducers (TRC051384, or tubastatin A) delayed thrombus formation. Remarkably, Hsp70 inducers did not increase the bleeding risk even when aspirin was concomitantly administered. Hsp70 induction was associated with an increased vascular thrombomodulin expression, higher circulating levels of activated protein C (APC) upon thrombotic stimulus and increased protection against endothelial apoptosis. Thus, Hsp70 induction is a novel approach to delay thrombus formation with minimal bleeding risk, being especially promising in situations where there is a major bleeding hazard. Microarray analysis in peripheral blood cells includes eight patients with AF and stroke and eight AF subjects without stroke
2016-04-01 | E-GEOD-66724 | biostudies-arrayexpress
Project description:Microarray and quantitative real-time PCR (qRT-PCR) results showed that the Caspase-1 expression was increased while miR-513c-5p level was decreased substantially in DVT patients, and there was significant negative correlation between miR-513c-5p and Caspase-1. Knockdown of miR-513c-5p could aggravate DVT formation by enhancing Caspase-1-mediated pyroptosis, while overexpression of miR-513c-5p could alleviate DVT formation via inhibiting Caspase-1 expression. we identified pyroptosis of PBMCs with elevated expression of Caspase-1 in DVT patients. miRNA microarray analysis revealed miR-513c-5p as the most significantly down-regulated miRNA in DVT and the receiver operating characteristic (ROC) analysis showed that miR-513c-5p level could sensitively discriminate DVT from healthy controls.
2022-04-27 | GSE173461 | GEO
Project description:Unleashing the Potential: Myeloid-Specific STING Inhibition Mitigates Deep Vein Thrombosis
| PRJNA1040161 | ENA
Project description:Atrial fibrillation (AF) is a major risk factor for cardioembolic stroke. Anticoagulant drugs are effective in preventing AF-related stroke. However, the high frequency of anticoagulant-associated major bleeding is a major concern particularly when antiplatelet treatment is simultaneously administered. Here, microarray analysis in peripheral blood cells in eight patients with AF and stroke and eight AF subjects without stroke identified a stroke related gene expression pattern. HSPA1B, which encodes for heat-shock protein 70 kDa (Hsp70), was the most differentially expressed gene. This gene was downregulated in stroke subjects, a finding confirmed further in an independent AF cohort of 200 individuals. Hsp70 knock-out (KO) mice subjected to different thrombotic challenges developed thrombosis significantly earlier than their wild-type (WT) counterparts. In WT mice, Hsp70 inducers (TRC051384, or tubastatin A) delayed thrombus formation. Remarkably, Hsp70 inducers did not increase the bleeding risk even when aspirin was concomitantly administered. Hsp70 induction was associated with an increased vascular thrombomodulin expression, higher circulating levels of activated protein C (APC) upon thrombotic stimulus and increased protection against endothelial apoptosis. Thus, Hsp70 induction is a novel approach to delay thrombus formation with minimal bleeding risk, being especially promising in situations where there is a major bleeding hazard.
2016-04-01 | GSE66724 | GEO
Project description:Targeting coagulation cascade is a mainstay approach to therapy of thrombosis. One of the most prevalent complications of anticoagulation is a significant bleeding risk that can result in hospitalization. Recent studies on immunothrombosis (i.e. inflammation-linked thrombosis) proposed myeloid cells, especially neutrophils, to actively participate in thrombus formation through neutrophil extracellular traps (NETosis) and activation of inflammatory pathways. Here, we developed lipid nanoparticles (LNPs) with coagulation cascade-independent action that target neutrophils to alleviate venous thrombosis. A single intravenous dose of immunomodulatory metabolite itaconate (ITA)-bearing LNPs (ITA-LNPs) targeted >90% of bone marrow-resident neutrophils, but not macrophages or T lymphocytes. ITA-LNPs significantly diminished inflammation in cultured neutrophils and macrophages and improved survival in the mouse model of endotoxemia. When tested in an inferior vena cava ligation model of deep vein thrombosis, ITA-LNPs decreased the size and weight of thrombi as compared to control LNPs (Ctrl-LNPs). In addition, the thrombi from ITA-LNPs injected mice had significantly reduced neutrophil infiltration, decreased NETosis and interleukin-1 beta (IL-1β) expression. Intriguingly, one of the mechanisms through which this occurred was histone H4K12ac deacetylation, resulting in chromatin condensation and transcriptional repression of inflammatory genes and transcription factors involved in DNA damage response. Finally, we found that ITA-LNPs were hemostatically safe and neither targeted nor activated platelets in vivo. In sum, our work explores an LNP technology with an epigenetic mode of action serving as an anti-immunothrombotic therapy that could improve clinical outcomes without additional hemorrhagic risk.
2025-07-18 | GSE283897 | GEO