Epigenetic repression of THBD transcription by BRG1 contributes to deep vein thrombosis

Wang, Teng; Kong, Ming; Xin, Xiaojun; Liu, Rui-qi; Wang, Hui-di; Song, Mingzi; Xu, Wenping; Yuan, Ye; Yang, Yuyu; Xiao, Pingxi

doi:10.1016/j.thromres.2022.09.015

Cited by 6 publications

(4 citation statements)

References 48 publications

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“…Our findings demonstrated that PFI-3 produced concentration-dependent vasorelaxation in both intact and denuded endothelium induced by PE and KPSS. As previous studies showed that PFI-3 can alleviate the expression of IL-6 and CCL2 ( Zhang et al, 2020 ) and the down-regulation of thrombomodulin in endothelial cells ( Wu et al, 2022 ), we assumed PFI-3-mediated vasorelaxation depends on the vascular endothelium. Unexpectedly, we observed that PFI-3 induced vasorelaxation in mesenteric arterial ring independent of endothelium, and further experiments showed that NO/sGC/cGMP pathway was not involved in PFI-3-induced vasorelaxation.…”

Section: Discussionmentioning

confidence: 99%

“… Zhang et al (2020) demonstrated that PFI-3 inhibited the inflammatory response by alleviating tumor necrosis factor- α -induced IL-6 and CCL2 expression, decreasing c-Fos expression, and blocking c-Fos translocation into nuclei. Moreover, Wu et al (2022) found that PFI-3 treatment alleviated the downregulation of thrombomodulin in endothelial cells and reduced the incidence of deep vein thrombosis induced by surgical procedures in mice.…”

Section: Introductionmentioning

confidence: 95%

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PFI-3 induces vasorelaxation with potency to reduce extracellular calcium influx in rat mesenteric artery

Liang

et al. 2023

PeerJ

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Background PFI-3 is a small-molecule inhibitor that targets the bromodomains (BRDs) of Brahma-related gene 1 (BRG1). This monomeric compound, which has high selectivity and potent cellular effects, has recently been developed. Although PFI-3 has been reported as a potential therapeutic agent targeting thrombomodulin, its role in the regulation of vascular function remains unknown. Therefore, we aimed to investigate the impact of PFI-3 on arterial vessel tone. Methods A microvascular tension measurement device (DMT) was utilized to identify alterations in vascular tension within the mesenteric artery. To detect variations in cytosolic [Ca2+]i, a Fluo-3/AM fluorescent probe and fluorescence microscope were employed. Additionally, whole-cell patch clamp techniques were utilized to evaluate the activity of L-type voltage-dependent calcium channels (VDCCs) in cultured arterial smooth muscle cells (A10 cells). Results PFI-3 exerted a dose-dependent relaxation effect on rat mesenteric arteries with both intact and denuded endothelium after phenylephrine (PE)- and high-K+-induced constriction. PFI-3-induced vasorelaxation was not affected by the presence of L-NAME/ODQ or K+ channel blockers (Gli/TEA). PFI-3 abolished Ca2+-induced contraction on endothelium-denuded mesenteric arteries preincubated by PE in Ca2+-free solution. Incubation with TG had no impact on PFI-3-induced vasorelaxation pre-contracted by PE. PFI-3 reduced Ca2+-induced contraction on endothelium-denuded mesenteric arteries pre-incubated by KCl (60 mM) in Ca2+-free solution. PFI-3 declined extracellular calcium influx in A10 cells detected by Fluo-3/AM fluorescent probe and fluorescence microscope. Furthermore, we observed that PFI-3 decreased the current densities of L-type VDCC by whole-cell patch clamp techniques. Conclusions PFI-3 blunted PE and high K+-induced vasoconstriction independent of endothelium on rat mesenteric artery. The vasodilatory effect of PFI-3 may be attributed to its inhibition of VDCCs and receptor-operated calcium channels (ROCCs) on vascular smooth muscle cells (VSMCs).

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

PFI-3 induces vasorelaxation with potency to reduce extracellular calcium influx in rat mesenteric artery

Liang

et al. 2023

PeerJ

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“…Human embryonic kidney cells (HEK293) were maintained in DMEM supplemented with 10% fetal bovine serum (FBS, HyClone) as previously described 27 , 28 . Primary murine renal fibroblasts were isolated and cultured as previously described 29 .…”

Section: Methodsmentioning

confidence: 99%

An MRTF-A–ZEB1–IRF9 axis contributes to fibroblast–myofibroblast transition and renal fibrosis

et al. 2023

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Myofibroblasts, characterized by the expression of the matricellular protein periostin (Postn), mediate the profibrogenic response during tissue repair and remodeling. Previous studies have demonstrated that systemic deficiency in myocardin-related transcription factor A (MRTF-A) attenuates renal fibrosis in mice. In the present study, we investigated the myofibroblast-specific role of MRTF-A in renal fibrosis and the underlying mechanism. We report that myofibroblast-specific deletion of MRTF-A, achieved through crossbreeding Mrtfa-flox mice with Postn-CreERT2 mice, led to amelioration of renal fibrosis. RNA-seq identified zinc finger E-Box binding homeobox 1 (Zeb1) as a downstream target of MRTF-A in renal fibroblasts. MRTF-A interacts with TEA domain transcription factor 1 (TEAD1) to bind to the Zeb1 promoter and activate Zeb1 transcription. Zeb1 knockdown retarded the fibroblast–myofibroblast transition (FMyT) in vitro and dampened renal fibrosis in mice. Transcriptomic assays showed that Zeb1 might contribute to FMyT by repressing the transcription of interferon regulatory factor 9 (IRF9). IRF9 knockdown overcame the effect of Zeb1 depletion and promoted FMyT, whereas IRF9 overexpression antagonized TGF-β-induced FMyT. In conclusion, our data unveil a novel MRTF-A–Zeb1–IRF9 axis that can potentially contribute to fibroblast–myofibroblast transition and renal fibrosis. Screening for small-molecule compounds that target this axis may yield therapeutic options for the mollification of renal fibrosis.

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“…Primary murine hepatocytes were isolated as previously described [ 25 – 27 ]. HEK293 cells were maintained in DMEM supplemented with 10% FBS as previously described [ 28 , 29 ].…”

Section: Methodsmentioning

confidence: 99%

TRIB1 regulates liver regeneration by antagonizing the NRF2-mediated antioxidant response

et al. 2023

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Robust regenerative response post liver injuries facilitates the architectural and functional recovery of the liver. Intrahepatic redox homeostasis plays a key role in liver regeneration. In the present study, we investigated the contributory role of Tribbles homolog 1 (Trib1), a pseudokinase, in liver regeneration and the underlying mechanism. We report that Trib1 expression was transiently down-regulated in animal and cell models of liver regeneration. Further analysis revealed that hepatocyte growth factor (HGF) repressed Trib1 transcription by evicting liver X receptor (LXRα) from the Trib1 promoter. Knockdown of Trib1 enhanced whereas over-expression of Trib1 suppressed liver regeneration after partial hepatectomy in mice. Of interest, regulation of liver regenerative response by Trib1 coincided with alterations of intracellular ROS levels, GSH levels, and antioxidant genes. Transcriptional assays suggested that Trib1 influenced cellular redox status by attenuating nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Mechanistically, Trib1 interacted with the C-terminus of Nrf2 thus masking a potential nuclear localization signal (NLS) and blocking nuclear accumulation of Nrf2. Finally, correlation between Trib1 expression, Nrf2 nuclear localization, and cell proliferation was identified in liver specimens taken from patients with acute liver failure. In conclusion, our data unveil a novel pathway that depicts Trib1 as a critical link between intracellular redox homeostasis and cell proliferation in liver regeneration.

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Epigenetic repression of THBD transcription by BRG1 contributes to deep vein thrombosis

Cited by 6 publications

References 48 publications

PFI-3 induces vasorelaxation with potency to reduce extracellular calcium influx in rat mesenteric artery

PFI-3 induces vasorelaxation with potency to reduce extracellular calcium influx in rat mesenteric artery

An MRTF-A–ZEB1–IRF9 axis contributes to fibroblast–myofibroblast transition and renal fibrosis

TRIB1 regulates liver regeneration by antagonizing the NRF2-mediated antioxidant response

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