Sphingomyelin synthase 2 over-expression induces expression of aortic inflammatory biomarkers and decreases circulating EPCs in ApoE KO mice
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Pregnancy is often referred to as a hypercoagulable state due to changes in the haemostatic system. Tissue factor (TF) is the initiator of blood clotting in vivo. The effect of pregnancy on monocyte TF expression was determined in a longitudinal case control study (89 pregnant, 39 non-pregnant). Using whole blood flow cytometry and CD14 as a monocyte marker, TF expression was measured on all CD14 positive, CD14Bright and CD14Dim cells. TF expression was significantly lower in pregnant women than in non-pregnant control subjects, on all CD14 positive cells at 20 and 35 weeks, on CD14Bright cells at 12 and 35 weeks and on CD14Dim cells at 20 weeks. Additionally, we report that a higher percentage of CD14Dim than CD14Bright cells express TF. These results suggest that, in order to maintain homeostasis in haemostasis in an otherwise hypercoagulable state, monocyte TF expression is reduced during normal pregnancy.
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Lipid-laden macrophages present as foam cells may contribute to the hyperthrombotic state of human atherosclerotic lesions by the production of tissue factor (TF). We investigated the effect of exogenous nonlipoprotein cholesterol on the expression of TF by human monocyte-derived macrophages in culture. Nonlipoprotein cholesterol at 50 micrograms/ml increased TF activity 4-fold; TF induction was dose- and time-dependent. Expression of TF activity was positively correlated with the free cholesterol content of monocyte-derived macrophages, was increased upon inhibition of cholesterol esterification, and reflected de novo synthesis of TF protein. TF expression in cholesterol-loaded macrophages remained sensitive to stimulation (approximately 12-fold) by bacterial lipopolysaccharide, indicating that intracellular free cholesterol and lipopolysaccharide act by distinct mechanisms in inducing TF procoagulant activity. Our results suggest that loading human monocyte-derived macrophages with free cholesterol induces upregulation of TF expression, thereby contributing to thrombus formation at sites of plaque rupture.
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Accelerated coronary atherosclerosis in cardiac allografts is a major factor limiting survival after heart transplantation, and activation of the coagulation system contributes to accelerated transplant atherosclerosis. Accordingly, increased tissue factor (TF) expression by monocyte/macrophages may play a pivotal role underlying deposition of fibrin in the affected vessels. To evaluate the potential effects of an important immunosuppressive agent, tacrolimus hydrate (FK-506), on monocyte/macrophages and their response to lipopolysaccharide (LPS), we exposed human monocyte/macrophage cell line (THP-1 cells), to LPS and characterized its procoagulant activity (PCA). FK-506 exerted a concentration-dependent inhibitory effect on LPS (10 micrograms/ml) induction of procoagulant activity, identified as TF activity as judged from immunostaining of TF antigen and by functional characterization with the use of coagulation factor VII-deficient plasma and an antibody against human TF. In addition, the reverse transcription polymerase chain reaction demonstrated reduced expression of TF mRNA in LPS-stimulated THP-1 cells exposed to FK-506. Thus, FK-506 acts favorably not only as a direct immunomodulating agent but also as an alleviator of local activation of the coagulation cascade contributing to transplant arteriopathy through modulation of monocyte expression of TF.
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Factor VIIa (F. VIIa)/tissue factor (TF) function was examined using purified human TF reconstituted into mixed phospholipid vesicles and TF expressed on cultured human umbilical vein endothelial cells (HUVEC) treated with thrombin. In reaction mixtures containing either type of TF, F. VIIa, 10 nM, either 3H-factor X or 3H-factor IX, 88 nM, and Ca2+, 5 mM, F. VIIa/TF activated factor X (F. X) several fold faster than it activated factor IX (F. IX). Adding heparin, 1 U/ml, increased rates of activation of both substrates and F. X remained the preferred substrate. Adding plasma at concentrations of 5% or above inhibited factor VIIa/TF catalytic activity. Inhibition was shown to require F. Xa as a cofactor, was prevented by antibodies to extrinsic pathway inhibitor (EPI), and was reversible by decalcification. Thus, with factor VIIa/TF formed with both types of TF, EPI appeared responsible for inhibition induced by plasma. Our data indicate that functional properties of factor VIIa/TF as delineated in reaction mixtures made with purified TF reconstituted into mixed phospholipid vesicles also hold for factor VIIa/TF activity on the surface of cultured HUVEC.
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Monocyte tissue factor expression was evaluated in 67 patients with hepatosplenic Schistosomiasis. They were classified as Child A (n = 15), Child B (n = 15), Child C (n = 12) and Bleeders (n = 10), in addition to 15 healthy controls. Mononuclear cells were cultured in vitro with and without lipopolysaccharide (LPS) to assess monocyte tissue factor (TF) antigen (Ag) and activity (Act) in cell lysate, in addition to measurement of prothrombin fragment 1 + 2 (F1 + 2) as a marker of in vivo thrombin generation. A significant increase in monocyte TF Ag and TF Act was noted in all stages of the disease compared with the control group, with marked accentuation during an acute attack of variceal bleeding. This enhanced monocyte expression was noted before the addition of LPS and became more obvious with addition of LPS. An increasing level of F1 + 2 was similarly noted. These findings constitute further evidence for an existing prothrombotic state in hepatosplenic Schistosomiasis, and also that monocytes are closely implicated in the haemostatic diathesis characterizing the disease.
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Summary Monocytes can be induced to express both tissue factor (TF) and its inhibitor, TF pathway inhibitor‐1 (TFPI‐1). A short incubation (<6 h) with interleukin (IL)‐4 and IL‐10, two potent deactivators of monocyte functions, has been shown to modulate the synthesis and expression of TF by monocytes activated by lipopolysaccharide, but the consequences of longer incubations (up to 96 h) on both TF and TFPI‐1 are unknown. The results of this study showed that adherent monocytes in culture spontaneously expressed TF and TFPI and that prolonged incubation with IL‐10 induced a time‐ and dose‐dependent decrease of monocyte TF synthesis, and an accumulation of TF/TFPI‐1 complexes at the moncyte surface, suggesting a decreased clearance of these complexes. In contrast, IL‐4 induced a time‐ and dose‐dependent increase in TF synthesis, which remained intracytoplasmic, as shown by confocal microscopy. Surprisingly, TF:antigen (Ag) was decreased at the monocyte surface, but the procoagulant activity (PCA) of IL‐4‐treated monocytes was increased, as a result of more pronounced decrease of TFPI‐1:Ag expression than that of TF. In conclusion, prolonged incubation with IL‐4 and IL‐10 oppositely modified PCA of cultured monocytes, and altered TF and TFPI trafficking and clearance. These data explain the respective deleterious or benefit effects of IL‐4 or IL‐10 in atherothrombosis.
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Background Fibrin deposition and thrombosis have been implicated in both allograft rejection and vasculopathy after cardiac transplantation. Because monocytes play a pivotal role in the pathophysiology of intravascular coagulation activation through their ability to synthesize tissue factor (TF), we asked (1) whether monocyte TF activation occurs in cardiac transplant recipients and (2) whether monocyte TF expression is affected by treatment with cyclosporin A (CsA). Methods and Results We measured levels of TF activity in peripheral blood mononuclear cells and highly purified monocytes/macrophages from 10 consecutive cardiac transplant recipients and 10 healthy control subjects. TF activity generated by both unstimulated and endotoxin-stimulated cells was significantly higher in transplant recipients than in control subjects ( P <.05). Increased monocyte TF expression in transplant recipients was shown to be adversely affected by treatment with CsA: TF induction was markedly reduced by CsA serum concentrations reaching peak CsA drug levels. Inhibition of TF induction in the presence of high CsA blood concentrations was also observed when stimulation of cells was performed with interferon-γ or interleukin-1β. As shown by reverse transcription–polymerase chain reaction and electrophoretic mobility shift assay, respectively, treatment with CsA leads to decreased TF mRNA expression and reduced activation of the NF-κB transcription factor, which is known to contribute to the induction of the TF promotor in human monocytes. Conclusions This study demonstrates that TF activation, occurring in mononuclear cells of cardiac transplant recipients, is inhibited by treatment with CsA. Inhibition of monocyte TF induction by CsA may contribute to its successful use in cardiac transplant medicine and might be useful in managing further settings of vascular pathology also known to involve TF expression and NF-κB activation.
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