Alterations in myocardial tissue factor expression and cellular localization in dilated cardiomyopathy

Szotowski, Björn; Goldin-Lang, Petra; Antoniak, Silvio; Bogdanov, Vladimir Y.; Pathirana, Delano; Pauschinger, Matthias; Dörner, Andrea; Kuehl, Uwe; Coupland, Sarah E.; Nemerson, Yale; Hummel, Michael; Poller, Wolfgang; Hetzer, Roland; Schultheiss, Heinz‐Peter; Rauch, Ursula

doi:10.1016/j.jacc.2004.12.061

Cited by 74 publications

(86 citation statements)

References 25 publications

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“…In each sample, full-length TF (TF), alternatively spliced TF (asTF), and GAPDH mRNA sequence-specific primers and probes for detection were applied as previously described (32): To amplify the two TF isoforms separately, the primers and probe for the detection of TF were designed to hybridize to exon 5, which is missing in asTF, whereas the asTF primers were designed to hybridize to exons 4 and 6, with the probe covering the unique exon 4/6 boundary, which is present in asTF (32). Two microliters of each cDNA (prepared from 0.5 g of total RNA), was added to a final PCR mix volume of 25 l that contained 12.5 l TaqMan Universal Master Mix (Applied Biosystems), 0.5 l (10 M) of each primer (Biolegio), 0.5 l (10 M) of probe, and 11.5 l of H 2 O. Real-time PCR was performed using the MiniOpticon Real-Time Detection System (BioRad) under the following conditions: 50°C for 2 min; 95°C for 10 min; 40 cycles of 95°C for 15 s and 60°C for 1 min.…”

Section: Rna Extraction and Semiquantitative Rt-pcr Analysis Of Tf Mrmentioning

confidence: 99%

A Novel C5a Receptor-Tissue Factor Cross-Talk in Neutrophils Links Innate Immunity to Coagulation Pathways

Ritis

Doumas

Mastellos

et al. 2006

The Journal of Immunology

416

338

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Neutrophils and complement are key sentinels of innate immunity and mediators of acute inflammation. Recent studies have suggested that inflammatory processes modulate thrombogenic pathways. To date, the potential cross-talk between innate immunity and thrombosis and the precise molecular pathway by which complement and neutrophils trigger the coagulation process have remained elusive. In this study, we demonstrate that antiphospholipid Ab-induced complement activation and downstream signaling via C5a receptors in neutrophils leads to the induction of tissue factor (TF), a key initiating component of the blood coagulation cascade. TF expression by neutrophils was associated with an enhanced procoagulant activity, as verified by a modified prothrombin time assay inhibited by anti-TF mAb. Inhibition studies using the complement inhibitor compstatin revealed that complement activation is triggered by antiphospholipid syndrome (APS) IgG and leads to the induction of a TF-dependent coagulant activity. Blockade studies using a selective C5a receptor antagonist and stimulation of neutrophils with recombinant human C5a demonstrated that C5a, and its receptor C5aR, mediate the expression of TF in neutrophils and thereby significantly enhance the procoagulant activity of neutrophils exposed to APS serum. These results identify a novel cross-talk between the complement and coagulation cascades that can potentially be exploited therapeutically in the treatment of APS and other complement-associated thrombotic diseases.

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Section: Rna Extraction and Semiquantitative Rt-pcr Analysis Of Tf Mrmentioning

confidence: 99%

A Novel C5a Receptor-Tissue Factor Cross-Talk in Neutrophils Links Innate Immunity to Coagulation Pathways

Ritis

Doumas

Mastellos

et al. 2006

The Journal of Immunology

416

338

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“…In 2003, Bogdanov et al described an alternatively spliced form of TF (asTF), which lacks a transmembrane domain and is present as a soluble protein [1]. asTF is produced by various cell types [1][2][3] and was reported to be present in human plasma, suggesting that asTF is secreted [1]. At present, the coagulant properties of asTF are disputed.…”

mentioning

confidence: 99%

“…The Gla domain binds eight calcium cations (Ca 2+ ) that are coordinated to 12 ccarboxyglutamate residues [2]. The EGF1 domain contains a single Ca 2+ -binding site that is coordinated to Asp47, Gln50, Asp64, and the backbone carbonyls of Gly48 and Asp65 [3]. The protease domain also contains a single Ca 2+ -binding site that is coordinated to Glu235, Glu245, and backbone carbonyls of residues 237 and 240 [4].…”

mentioning

confidence: 99%

Human alternatively spliced tissue factor is not secreted and does not trigger coagulation

Böing

Hau

Sturk

et al. 2009

Journal of Thrombosis and Haemostasis

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1-74) in patients (n = 68) with normal MP-TF activity (P = 0.028). In the group of 51 patients who presented with VTE, survival was significantly worse in patients with elevated MP-TF activity than in those with normal MP-TF activity (P = 0.010). In univariate analysis only tumour type, thrombosis and MP-TF activity were significantly associated with survival. In multivariate analysis, adjustment for tumour type, age and stage, did not affect the association between MP-TF activity and mortality (P < 0.015).The present study is the largest series of unselected patients with both cancer and VTE, in whom MP-TF activity has been measured in the acute phase of thrombosis. The strength of the present study is that we did not select for any tumour type but instead investigated all cancer patients who presented with acute VTE irrespective of the type of malignancy. We observed that MP-TF activity in cancer patients with VTE is higher than in matched cancer patients without VTE. This finding strongly supports previous observations of a relationship between elevated MP-TF activity and VTE in patients with cancer from small studies of selected cancer patients [1,[4][5][6].It is interesting that the large majority of patients who develop VTE during chemotherapy have normal MP-TF activity, suggesting that an acute thrombotic event itself is not the cause of an elevated MP-TF activity. Our data point to a contribution of cancer cells themselves as (in) direct cause of elevated MP-TF activity and ask for novel studies better designed to study prospectively the relationship between chemotherapy, elevated MP-TF activity and venous thrombosis. AcknowledgementsThis study was financially supported by a grant of the Dutch Cancer Foundation KWF/NKB UL-2006-3618. Disclosure of Conflict of InterestsThe authors state that they have no conflict of interest.

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“…58 TF is down-regulated in the myocardium of patients with dilated cardiomyopathy (DCM). 59 Myocardial specimens from DCM hearts show that it has an altered cell localisation, being 60 redistributed from the Z-bands to the perinuclear cytosol [9]. This further suggests that decreased 61 TF expression and change in localisation may affect contractility and cell-to-cell contact stability, 62 thus contributing to cardiac dysfunction in patients with DCM [9].…”

Section: Introduction 45mentioning

confidence: 99%

“…59 Myocardial specimens from DCM hearts show that it has an altered cell localisation, being 60 redistributed from the Z-bands to the perinuclear cytosol [9]. This further suggests that decreased 61 TF expression and change in localisation may affect contractility and cell-to-cell contact stability, 62 thus contributing to cardiac dysfunction in patients with DCM [9]. 63 The in vitro and in vivo administration of lipopolysaccharide reduces TF mRNA and protein 64 expression in cardiomyocytes, but not in lung, kidney or brain [6,10,11], which not only clearly 65 demonstrates that TF is uniquely regulated in the heart, but also suggests that it has potentially 66 unique functions in heart morphogenesis and the maintenance of cardiac muscle structure.…”

Section: Introduction 45mentioning

confidence: 99%

Proteomics of tissue factor silencing in cardiomyocytic cells reveals a new role for this coagulation factor in splicing machinery control

Lento

Brioschi

Barcella

et al. 2015

Journal of Proteomics

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22It has long been known that Tissue Factor (TF) plays a role in blood coagulation and has a direct 23 thrombotic action that is closely related to cardiovascular risk, but it is becoming increasingly 24clear that it has a much wider range of biological functions that range from inflammation to 25 immunity. It is also involved in maintaining heart hemostasis and structure, and the observation 26 that it is down-regulated in the myocardium of patients with dilated cardiomyopathy suggests that 27 it influences cell-to-cell contact stability and contractility, and thus contributes to cardiac 28 dysfunction. However, the molecular mechanisms underlying these coagulation-independent 29 functions have not yet been fully elucidated. 30In order to analyse the influence of TF on the cardiomyocitic proteome, we used functional 31 biochemical approaches incorporating label-free quantitative proteomics and gene silencing, and 32found that this provided a powerful means of identifying a new role for TF in regulating splicing 33 machinery together with the expression of several proteins of the spliceosome, and mRNA 34 metabolism with a considerable impact on cell viability. 35 36 SIGNIFICANCE 37

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Alterations in myocardial tissue factor expression and cellular localization in dilated cardiomyopathy

Abstract: Tissue factor was down-regulated in the myocardium of DCM patients. The reduction in TF expression and change in localization may influence cell-to-cell contact stability and contractility, thereby contributing to cardiac dysfunction in DCM.

Cited by 74 publications

References 25 publications

A Novel C5a Receptor-Tissue Factor Cross-Talk in Neutrophils Links Innate Immunity to Coagulation Pathways

A Novel C5a Receptor-Tissue Factor Cross-Talk in Neutrophils Links Innate Immunity to Coagulation Pathways

Human alternatively spliced tissue factor is not secreted and does not trigger coagulation

Proteomics of tissue factor silencing in cardiomyocytic cells reveals a new role for this coagulation factor in splicing machinery control

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