NF-κB Transcription Factor p50 Critically Regulates Tissue Factor in Deep Vein Thrombosis

Li, Yi Dan; Ye, Bu Qing; Xi, Zheng, Sheng; Wang, Liangjing; Wang, Jingguo; Chen, Ming; Guo, Liu, Ji; Pei, Xin; Wang, Lijing; Lin, Zhi Lin; Gupta, Kalpna; Mackman, Nigel; Slungaard, Arne; Key, Nigel S.; Geng, Jian Guo

doi:10.1074/jbc.m806010200

Cited by 84 publications

(81 citation statements)

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“…There are binding sites for four transcription factors in this region as follows: AP-1, NF-B, Egr-1, and Sp1. Sp1 is required for constitutive TF gene tran-scription, although the other three are responsible for inducible TF gene transcription (21). Although Egr-1 is an immediate early gene product, our previous study showed that de novo protein synthesis is not required for P2Y2R-mediated TF induction (11).…”

Section: P2y2r Activation Boosts Tf Expression By Promoting Genementioning

confidence: 95%

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Purinergic P2Y2 Receptor Control of Tissue Factor Transcription in Human Coronary Artery Endothelial Cells

Liu

Zhang

Wang

et al. 2016

Journal of Biological Chemistry

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We recently reported that the P2Y2 receptor (P2Y2R) is the predominant nucleotide receptor expressed in human coronary artery endothelial cells (HCAEC) and that P2Y2R activation by ATP or UTP induces dramatic up-regulation of tissue factor (TF), a key initiator of the coagulation cascade. However, the molecular mechanism of this P2Y2R-TF axis remains unclear. Here, we report the role of a newly identified AP-1 consensus sequence in the TF gene promoter and its original binding components in P2Y2R regulation of TF transcription. Using bioinformatics tools, we found that a novel AP-1 site at ؊1363 bp of the human TF promoter region is highly conserved across multiple species. Activation of P2Y2R increased TF promoter activity and mRNA expression in HCAEC. Truncation, deletion, and mutation of this distal AP-1 site all significantly suppressed TF promoter activity in response to P2Y2R activation. EMSA and ChIP assays further confirmed that upon P2Y2R activation, c-Jun, ATF-2, and Fra-1, but not the typical c-Fos, bound to the new AP-1 site. In addition, loss-of-function studies using siRNAs confirmed a positive transactivation role of c-Jun and ATF-2 but unexpectedly revealed a strong negative role of Fra-1 in P2Y2R-induced TF up-regulation. Furthermore, we found that P2Y2R activation promoted ERK1/2 phosphorylation through Src, leading to Fra-1 activation, whereas Rho/JNK mediated P2Y2R-induced activation of c-Jun and ATF-2. These findings reveal the molecular basis for P2Y G protein-coupled receptor control of endothelial TF expression and indicate that targeting the P2Y2R-Fra-1-TF pathway may be an attractive new strategy for controlling vascular inflammation and thrombogenicity associated with endothelial dysfunction.Nucleotides matter more than being the universal currency of energy transaction and the building blocks of genes. They are also short term signaling molecules and long term trophic factors through P2X or P2Y receptors (1). Among the eight G protein-coupled P2Y nucleotide receptors, the ADP-preferring

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Section: P2y2r Activation Boosts Tf Expression By Promoting Genementioning

confidence: 95%

“…2A) (21). There are binding sites for four transcription factors in this region as follows: AP-1, NF-B, Egr-1, and Sp1.…”

Section: P2y2r Activation Boosts Tf Expression By Promoting Genementioning

confidence: 99%

Purinergic P2Y2 Receptor Control of Tissue Factor Transcription in Human Coronary Artery Endothelial Cells

Liu

Zhang

Wang

et al. 2016

Journal of Biological Chemistry

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“…Therefore, care must be taken to interpret the physiological relevance of these results. The infusion of an anti-PDI antibody also abolished the enhanced thrombus formation, suggesting that PDI-induced TF decryption may play a role in 84 Ab to TF inhibits thrombus formation 67 TF in histological sections 19 TF in histological sections 24 TF in histological sections 49 and thrombus formation is blocked by NF-B inhibitor 48 Low-TF mouse Cardiac fibrosis 23 Decreased thrombus formation 7 NR NR Delayed occlusion 24 Decreased thrombus size 24 Low A summary of the known data regarding the role of TF in thrombus formation using the low-TF mouse, cardiomyocyte TF-deficient mouse (TF flox/flox /MLC2v-Cre), vascular SM cell TF-deficient mouse (TF flox/flox /SM22␣-Cre), hematopoietic and endothelial cell TF-deficient mice (TF flox/flox /Tie2-Cre), or the hTF mouse. Wild-type and low-TF mouse chimeras were also made by transplanting bone marrow from one into the other to investigate the role of hematopoietic cell TF to thrombus formation in each injury model.…”

Section: Arterial Ligation Modelsmentioning

confidence: 96%

“…37 IVC ligation-induced thrombosis is reduced by andrographolide, a p50 inhibitor. 48 Andographolide blocks nuclear factor-B-induced TF expression in endothelial cells and leukocytes, suggesting that the nuclear factor-B transcription factor, p50, is important in the pathogenesis of DVT. Recently, Zhou et al 49 measured the extent of thrombus formation 15 and 60 minutes after IVC ligation in rats.…”

Section: Venous Ligation Modelsmentioning

confidence: 99%

Tissue Factor and Thrombosis Models

Kretz

Vaezzadeh

Gross

2010

ATVB

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“…Systemic delivery of miR-181b or Card10 siRNA delays development of thrombosis in vivo TF is a critical regulator of arterial thrombosis (27) and an NF-kB-responsive target gene (28,29). Unsurprisingly, miR-181b also inhibited expression of TF (Supplemental Fig.…”

Section: Card10 Knockdown Has No Effect On Tnf-a-induced Gene Expressmentioning

confidence: 99%

MicroRNA‐181b inhibits thrombin‐mediated endothelial activation and arterial thrombosis by targeting caspase recruitment domain family member 10

Lin

Sun

et al. 2016

FASEB j.

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Thrombogenic and inflammatory mediators, such as thrombin, induce NF-kB-mediated endothelial cell (EC) activation and dysfunction, which contribute to pathogenesis of arterial thrombosis. The role of anti-inflammatory microRNA-181b (miR-181b) on thrombosis remains unknown. Our previous study demonstrated that miR-181b inhibits downstream NF-kB signaling in response to TNF-a. Here, we demonstrate that miR-181b uniquely inhibits upstream NF-kB signaling in response to thrombin. Overexpression of miR-181b inhibited thrombin-induced activation of NF-kB signaling, demonstrated by reduction of phospho-IKK-b, -IkB-a, and p65 nuclear translocation in ECs. MiR-181b also reduced expression of NF-kB target genes VCAM-1, intercellular adhesion molecule-1, E-selectin, and tissue factor. Mechanistically, miR-181b targets caspase recruitment domain family member 10 (Card10), an adaptor protein that participates in activation of the IKK complex in response to signals transduced from protease-activated receptor-1. miR-181b reduced expression of Card10 mRNA and protein, but not protease-activated receptor-1. 39-Untranslated region reporter assays, argonaute-2 microribonucleoprotein immunoprecipitation studies, and Card10 rescue studies revealed that Card10 is a bona fide direct miR-181b target. Small interfering RNA-mediated knockdown of Card10 expression phenocopied effects of miR-181b on NF-kB signaling and targets. Card10 deficiency did not affect TNF-a-induced activation of NF-kB signaling, which suggested stimulus-specific regulation of NF-kB signaling and endothelial responses by miR-181b in ECs. Finally, in response to photochemical injuryinduced arterial thrombosis, systemic delivery of miR-181b reduced thrombus formation by 73% in carotid arteries and prolonged time to occlusion by 1.6-fold, effects recapitulated by Card10 small interfering RNA. These data demonstrate that miR-181b and Card10 are important regulators of thrombin-induced EC activation and arterial thrombosis. These studies highlight the relevance of microRNA-dependent targets in response to ligand-specific signaling in

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NF-κB Transcription Factor p50 Critically Regulates Tissue Factor in Deep Vein Thrombosis

Cited by 84 publications

References 50 publications

Purinergic P2Y2 Receptor Control of Tissue Factor Transcription in Human Coronary Artery Endothelial Cells

Purinergic P2Y2 Receptor Control of Tissue Factor Transcription in Human Coronary Artery Endothelial Cells

Tissue Factor and Thrombosis Models

MicroRNA‐181b inhibits thrombin‐mediated endothelial activation and arterial thrombosis by targeting caspase recruitment domain family member 10

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