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Epigenetic metabolite lipid nanoparticles alleviate venous thrombosis via bone marrow reprogramming

ABSTRACT: Epigenetic metabolite lipid nanoparticles alleviate venous thrombosis via bone marrow reprogramming

PROVIDER: PRJNA1195983 | ENA |

REPOSITORIES: ENA

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Epigenetic metabolite lipid nanoparticles alleviate venous thrombosis via bone marrow reprogramming

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

A targetable pathway in neutrophils mitigates both arterial and venous thrombosis

Project description:Arterial and venous (A/V) thrombosis constitutes the greatest source of morbidity and mortality worldwide. Long considered as distinct entities, accumulating evidence indicates that A/V thrombosis can occur in the same populations suggesting that common mechanisms are likely operative. Although hyperactivation of the immune system is a common forerunner to the genesis of thrombotic events in both vascular systems, the key molecular control points remain poorly understood. Consequently, anti-thrombotic therapies targeting the immune system for therapeutic gain are lacking. Here we show that neutrophils are key effectors of both A/V thrombosis and can be targeted via novel immunoregulatory nanoparticles. Using antiphopholipid antibody syndrome (APS) as a model for devastating A/V thrombosis, we identified the transcription factor Krüppel-like factor 2 (KLF2) as a key regulator of neutrophil activation. Upon activation via genetic loss of KLF2 or administration of antiphospholipid antibodies, neutrophils cluster P-selectin glycoprotein ligand 1 (PSGL-1) via cortical actin remodeling, thereby increasing adhesion potential at thrombosis sites. Targeting clustered PSGL-1 using designer nanoparticles attenuates neutrophil-mediated A/V thrombosis in APS and KLF2 knockout models, illustrating the importance and feasibility of targeting activated neutrophils to prevent pathological thrombosis. Together, our results demosntrate a role for activated neutrophils to prevent pathological thrombosis. Together, our results demonstrate a role for activated neutorphils in both arterial and venous thrombosis and identify key molecular events that serve as potential targets for therapeutics against diverse causes of immunothrombosis.

2022-09-12 | GSE208336 | GEO

GENEVA GWAS of Venous Thrombosis

Project description:GENEVA GWAS of Venous Thrombosis

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Interactive relationships between potential miRNAs and target mRNAs in deep venous thrombosis identified by RNA sequencing

Project description:Background: Deep venous thrombosis is one of the most common peripheral vascular diseases that lead to major morbidity and mortality. We aimed to identify potential differentially expressed miRNAs and target mRNAs, which were helpful in understanding the potential molecule mechanism of deep venous thrombosis.

2025-02-01 | GSE196751 | GEO

Transcriptomic Analysis of Long Non-coding RNAs and mRNAs in a Mouse Model of Venous Thrombosis

Project description:Recent advancements have identified numerous long non-coding RNAs (lncRNAs) involved in various biological processes and diseases. However, the roles of lncRNAs in venous thromboembolism (VTE) remain largely unexplored. This study aims to elucidate the expression profiles of lncRNAs and mRNAs in a well-established animal model of VTE. Acute thrombosis was induced by surgical ligation of the inferior vena cava (IVC) within 24 hours. The thrombus burden in venous vessels was evaluated using hematoxylin and eosin staining and Masson's trichrome staining. The IVC and associated thrombus were harvested 24 hours post-ligation, and the extracted RNA was subjected to RNA sequencing (RNA-seq) analysis. This study offers a comprehensive overview of the expression profiles of lncRNAs and mRNAs in a murine model of venous thrombosis, providing novel insights into the roles of RNAs in VTE.

2025-02-19 | GSE269352 | GEO

1α,25-Dihydroxyvitamin D3 encapsulated in Nanoparticles Prevents Venous Neointimal Hyperplasia and Stenosis in Porcine Arteriovenous Fistulas

Project description:1α,25-Dihydroxyvitamin D3 encapsulated in Nanoparticles Prevents Venous Neointimal Hyperplasia and Stenosis in Porcine Arteriovenous Fistulas

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Cell Adhesion Molecule 1 (CADM1): A Novel Risk Factor for Venous Thrombosis

Project description:Protein C (PC) deficiency increases the risk of venous thrombosis (VT) among members of Kindred Vermont II, but fails to fully account for the inheritance pattern. A genome scan of the pedigree supported the presence of a prothrombotic gene on chromosome 11q23 with weaker support on chromosomes 10p12 and 18p11.2-q11. Preliminary data from Affimetrix microarray expression analysis of Blood Outgrowth Endothelial Cells of 3 members of Kindred Vermont II compared to a well established normal control group indicated that IgsF4 was decreased in patients versus controls. In addition, both statistical and pathway analysis results suggested that these genes are associated protein C. Further studies indicated that Cell Adhesion Molecule 1 (CADM1), a member of the IgsF4 superfamily, may be associated with VT.

2009-07-15 | GSE17078 | GEO

A targetable pathway in neutrophils mitigates both arterial and venous thrombosis

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Single-cell RNA sequencing on the vein wall of mouse deep vein thrombosis

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

Expression and Possible Mechanism of circular RNA rno_CIRCpedia_1953 in Deep Venous Thrombosis

Project description:Expression and Possible Mechanism of circular RNA rno_CIRCpedia_1953 in Deep Venous Thrombosis

| PRJNA623908 | ENA