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- W4319433499 abstract "Abstract Objectives: Macrophages (Mϕs) are critical in the process of subacute and chronic venous thrombus (VT) resolution. Epigenetic alterations can reprogram Mϕ function in chronic inflammatory states. We hypothesized that the chromatin modifying enzyme MLL1/KMT2a, which increases H3K4 trimethylation at NF-kβ targeted promoters during inflammatory processes, influences Mϕ-mediated post-thrombotic fibrinolysis. Methods: Bone marrow derived Mϕs (BMDMs) from C57bl6 mice and immortalized Mϕs (RAW264.7) were used for in vitro experiments. Small interfering RNAs (siRNAs) were transfected to achieve MLL1 silencing, and qPCR, immunoblotting, and chromatin immunoprecipitation (ChIP) assays were performed. In vivo, VT formation was induced by IVC ligation, after which BMDMs were harvested. Results: Analysis of procoagulant and antifibrinolytic transcripts in MLL1 silenced BMDMs and RAW264.7 cells revealed suppression of urokinase (Plau) mRNA and protein levels by >80% and >50% respectively (p<0.05) relative to controls. ChIP analysis of the Plau promoter in MLL1 knockdown cells showed decreased enrichment (~4.6 fold, p=0.0216) of H3K4me3 and suggested a functional role for MLL1 to promote Plau expression. BMDMs harvested from mice 7 days post-thrombosis showed suppressed mRNA and protein levels of MLL1 (by >65% and >55% respectively, p<0.05), PLAU (by >85% and >55% respectively, p<0.05) levels and decreased H3K4me3 enrichment on the Plau promoter (~7.2 fold, p=0.0031) relative to controls. Conclusions: The post-thrombotic inflammatory state induces MLL1-mediated epigenetic modifications in the bone marrow, resulting in suppression of Mϕ urokinase expression. These changes may contribute to an antibrinolytic Mϕ phenotype." @default.
- W4319433499 created "2023-02-09" @default.
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- W4319433499 date "2021-05-01" @default.
- W4319433499 modified "2023-10-17" @default.
- W4319433499 title "Post-Thrombotic loss of the epigenetic enzyme MLL1/KMT2a in macrophages suppresses urokinase expression and may contribute to an antifibrinolytic phenotype" @default.
- W4319433499 doi "https://doi.org/10.4049/jimmunol.206.supp.95.04" @default.
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