Cell type–specific regulation of von Willebrand factor expression by the E4BP4 transcriptional repressor

Hough, Christine; Cuthbert, Carla; Notley, Colleen; Brown, Christine; Hegadorn, Carol; Berber, Ergül; Lillicrap, David

doi:10.1182/blood-2002-10-3093

Cited by 24 publications

(16 citation statements)

References 49 publications

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“…Common signaling pathways including NF-B or MAPKinase pathways do not appear to be involved (45). vWF expression and secretion appears to be modulated by distinct signaling pathways involving unknown transcription factors susceptible to interact with different regions of the vWF promoter (14). This could explain the absence of effect of PDTC on CRP-stimulated PAEC.…”

Section: Nf-b Partially Mediates the Effects Of Crp On Cells Of Ctephmentioning

confidence: 85%

NF-κB pathway is involved in CRP-induced effects on pulmonary arterial endothelial cells in chronic thromboembolic pulmonary hypertension

Wynants

Vengethasamy

Ronisz

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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Wynants M, Vengethasamy L, Ronisz A, Meyns B, Delcroix M, Quarck R. NF-B pathway is involved in CRP-induced effects on pulmonary arterial endothelial cells in chronic thromboembolic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 305: L934-L942, 2013. First published October 4, 2013 doi:10.1152/ajplung.00034.2013.-Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by thrombofibrotic obstruction of proximal pulmonary arteries. The cellular and molecular mechanisms underlying the pathogenesis remain incompletely understood, although we recently evidenced the potential involvement of the inflammatory marker C-reactive protein (CRP). We aimed to investigate the intracellular mechanisms induced by CRP in proximal pulmonary arterial endothelial cells (PAEC). PAEC were isolated from vascular material obtained during pulmonary endarterectomy. RNA was extracted from CRP-stimulated PAEC, and first-stand cDNA was generated. A RT 2 profiler PCR Array was used to evaluate the expression of 84 key genes related to NF-B-mediated signal transduction. CRP-induced NF-B activation was studied. The effects of pyrrolidine-dithio-carbamate ammonium (PDTC), an inhibitor of the NF-B pathway, were investigated on CRP-induced adhesion of monocytes to PAEC, adhesion molecule expression, endothelin-1 (ET-1), interleukin-6 (IL-6), and von Willebrand factor (vWF) secretion. Compared with nonstimulated PAEC, serotonin receptor 2B was downregulated by 25%, inhibitor of NF-B kinase subunit epsilon (IKBKE) by 30%, and toll-like receptor-4 and -6 by 18 and 39%, respectively, in CRP-stimulated PAEC. The transcription factor FOS was threefold upregulated. CRP induced RelA/NF-Bp65 phosphorylation. PDTC dose dependently inhibited the adhesion of monocytes to CRP-stimulated PAEC. PDTC also inhibited the CRP-induced expression of ICAM-1 at the surface of PAEC. PDTC impaired the secretion of ET-1 by 18% and tended to inhibit the secretion of IL-6 by CRP-stimulated PAEC by 46%. PDTC did not inhibit the CRP-induced secretion of vWF. These results suggest an involvement of the NF-B pathway in mediating different effects of CRP on proximal CTEPH-PAEC. C-reactive protein; endothelial cells; NF-B; chronic thromboembolic pulmonary hypertension CHRONIC THROMBOEMBOLIC PULMONARY hypertension (CTEPH) is a severe cause of pulmonary hypertension characterized by an obliteration of proximal pulmonary arteries by intraluminal thrombi and fibrous stenosis. Pulmonary embolism, either as single or recurrent episodes, is thought to be the initiating event followed by progressive pulmonary vascular remodeling. Vascular disobliteration by pulmonary endarterectomy (PEA) is the preferred treatment for CTEPH patients (38).Knowledge of the physiopathology of CTEPH remains incomplete. Proximal lesions share similarities with atherosclerotic plaques, including media thickening and neointima formation (1). Risk factors for CTEPH include size of the initial thrombus, elevated factor VIII, circulating phospholipid antibodies, and fibrinogen intrinsic ...

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Section: Nf-b Partially Mediates the Effects Of Crp On Cells Of Ctephmentioning

confidence: 85%

NF-κB pathway is involved in CRP-induced effects on pulmonary arterial endothelial cells in chronic thromboembolic pulmonary hypertension

Wynants

Vengethasamy

Ronisz

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Immunoprecipitates were recovered with magnetic protein G-coated beads and DNA was purified by means of Amersham PCR DNA and the Gel Band Purification kit (Amersham Biosciences). DNA fragments in the range from 200 to 1500 bp were analyzed by PCR using a pair of primers ((forward) 5Ј-GAAATAATTTTGCTTCCCCTCTTCCC-3Ј and (reverse) 5Ј-TCCTAGATCTCTTGCCTTAGAGCTACCTCC-3Ј) spanning the putative STAT3 and HNF-1␣ response elements in the CRP promoter (Ϫ133/ ϩ18), or a pair of primers for ␤-actin ((forward) 5Ј-TGCCTAGGTCAC CCACTAATG-3Ј and (reverse) 5Ј-GTGGCCCGTGATGAAGGCTA-3Ј) (38). The 2 l from a 20 l of DNA extraction was amplified for 40 cycles of 98°C for 10 s, 55°C for 30 s, and 72°C for 30 s.…”

Section: Chromatin Immunoprecipitation (Chip) Assaymentioning

confidence: 99%

Transcriptional Complex Formation of c-Fos, STAT3, and Hepatocyte NF-1α Is Essential for Cytokine-Driven C-Reactive Protein Gene Expression

Nishikawa

Hagihara

Serada

et al. 2008

The Journal of Immunology

113

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C-reactive protein (CRP) is a sensitive marker and mediator of inflammation, whereas IL-6 blocking therapy can normalize serum levels of CRP in chronic inflammatory diseases. We investigated the precise synergistic induction mechanism of CRP gene expression by IL-1 and IL-6 in Hep3B cells. In the early induction phase, IL-1 inhibited IL-6-mediated CRP gene expression, and NF-κB p65 inhibited the luciferase activity of pGL3-CRP by IL-1 plus IL-6 even in the presence of overexpressed STAT3. In the late induction phase, we focused on JNK and p38 activated by IL-1. SP600125 reduced the expression of the CRP gene induced by IL-1 plus IL-6. Unexpectedly, overexpression of c-Fos dramatically enhanced the luciferase activity by IL-1 and IL-6 even though the CRP gene has no AP-1 response element (RE) in its promoter. The augmentative effect of c-Fos required the presence of STAT3 and 3′-hepatocyte NF-1 (HNF-1) RE, which were eliminated by dominant negative STAT3 and HNF-1α, respectively. SB203580 inhibited the phosphorylation of c-Fos enhanced by IL-1 plus IL-6, and diminished expression of the CRP gene. Immunoprecipitation, Western blot analysis, the Supershift assay using a CRP oligonucleotide containing STAT3 and 3′-HNF-1 RE, and the chromatin immunoprecipitation assay demonstrated that c-Fos/STAT3/HNF-1α forms a complex on the CRP gene promoter. Because human fetus liver cells failed to express c-Fos/STAT3/HNF-1α showed no CRP production, transcriptional complex formation of c-Fos/STAT3/HNF-1α is essential for the synergistic induction of CRP gene expression by IL-1 plus IL-6. Our findings fully explain the clinical results of IL-6 blocking therapy and are expected to contribute to the development of a therapeutic strategy for chronic inflammatory diseases.

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“…An NFY probe was used as a control. 16 Mice biophotonic studies and analysis of organ-specific reporter gene expression Animal studies were approved by the Queen's University Animal Care Committee. Nine adult WT Balb/c mice were injected via the tail vein with 3.5 ϫ 10 10 viral particles of purified WT or Mut HD-Ad-VWF 24 hours after they had received an intravenous infusion of 250 L of clodronate liposomes.…”

Section: Emsasmentioning

confidence: 99%

Functional characterization of a 13-bp deletion (c.-1522_-1510del13) in the promoter of the von Willebrand factor gene in type 1 von Willebrand disease

Othman

Chirinian

Brown

et al. 2010

Blood

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Introductionvon Willebrand factor (VWF) is a multimeric adhesive glycoprotein that plays several key roles in hemostasis. It mediates platelet adhesion and aggregation at the sites of vascular injury, and acts as a carrier for coagulation factor VIII to protect it from proteolytic degradation. 1,2 VWF plasma levels below 50% are found in the most common type of von Willebrand disease (VWD), type 1 VWD, which is characterized by a mild/moderate deficiency of functionally normal VWF. The understanding of the genetic basis and molecular pathophysiology of type 1 VWD has been a challenge, and a heterogeneous array of VWF gene mutations, located throughout the gene, have been documented in these patients. The details of these mutations are listed and updated on the ISTH VWF SSC Database (http://www.sheffield.ac.uk/ VWF/index.html).Three large population studies of type 1 VWD patients have detailed the spectrum of VWF gene mutations in several European Countries and in Canada. However, candidate pathogenic VWF mutations were not found in 27%, 3 in 36%, 4 and in 28% 5 of index cases diagnosed with type 1 VWD. In the Canadian study, 8 sequence variations within the 5Ј regulatory region of the VWF gene were found after sequencing DNA from 123 index cases with type 1 VWD. These 5Ј regulatory sequence changes represented 16% of the total candidate mutations found in this study. However, to date, there has been no functional evidence to support the pathogenic nature of any of these sequence variations.Earlier VWF promoter studies have indicated that, in vitro, the basal transcription of the human VWF gene is mediated through a region in the promoter located between base pairs Ϫ89 and ϩ19 (relative to transcription start site, TSS ϩ1). This region was functional in both endothelial and nonendothelial cell types. 6 In vivo studies demonstrated that VWF sequences between Ϫ487 to ϩ247 are responsible for promoter activation in brain vascular endothelial cells. 7 The Ϫ60/ϩ19 region has been shown to be a critical area within the VWF gene promoter, possessing 2 Ets-binding motifs, with the 5Ј-most motif being more critical to transcriptional activation. 6 In transgenic mice, a larger VWF fragment (2182 bp) containing the 5Ј-flanking sequences and including exon 1 and intron 1 of the gene has been shown to activate transgene expression in endothelial cells of the heart, skeletal muscles, and brain, 8 suggesting that additional distant VWF gene sequences are required for expression in other vascular endothelial cells in vivo. Specific interaction between positive and negative regulatory sequences together with their transcription factors have been identified within this region and have contributed to the endothelial-specific VWF mRNA expression levels. 6,9,[10][11] The local vascular microenvironment also appears to contribute to the regulation of endothelial VWF expression, 8 and it is well recognized that there is considerable heterogeneity in the distribution and nature of endothelial VWF expression throughout the vasculature. 1...

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Cell type–specific regulation of von Willebrand factor expression by the E4BP4 transcriptional repressor

Abstract: Mechanisms

Cited by 24 publications

References 49 publications

NF-κB pathway is involved in CRP-induced effects on pulmonary arterial endothelial cells in chronic thromboembolic pulmonary hypertension

NF-κB pathway is involved in CRP-induced effects on pulmonary arterial endothelial cells in chronic thromboembolic pulmonary hypertension

Transcriptional Complex Formation of c-Fos, STAT3, and Hepatocyte NF-1α Is Essential for Cytokine-Driven C-Reactive Protein Gene Expression

Functional characterization of a 13-bp deletion (c.-1522_-1510del13) in the promoter of the von Willebrand factor gene in type 1 von Willebrand disease

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