HMG CoA reductase inhibitor suppresses the expression of tissue factor and plasminogen activator inhibitor-1 induced by angiotensin II in cultured rat aortic endothelial cells

Background. Tissue factor (TF) is a key element for normal gestation, especially in the first trimester. TF levels are hence raised in pregnancy, producing an adaptive hypercoagulable state. Potentiated hypercoagulability however, is associated with disorders of pregnancy such as pre-eclampsia but the results of TF and its inhibitor, tissue factor pathway inhibitor (TFPI), measurement, in pre eclampsic women are ambiguous and the data conflicting. This review covers the current knowledge status of the role of TF assessment in pregnancy with a focus on its diagnostic utility. Methods. A review of the literature using the following key words: tissue factor, thrombosis, inflammation, pregnancy, preeclampsia.Results. The published literature shows raised and unchanged TF levels in various studies of pre-eclampsia along with equally conflicting data for TFPI. The various study designs and methods used in these studies makes valid comparison difficult. Meta analysis of 34 randomized trials showed that low-dose aspirin in early phases of gravidity (starting from the 16th week or earlier) significantly reduces the incidence of preeclampsia. Conclusions. Overall, the results of the literature search together with knowledge of the structure and biological effects of TF, suggest that measuring the level of plasma TF/TFPI is not ideal for determining the actual levels of TF in the uteroplacental circulation. The current view that endothelial dysfunction is the trigger for preeclampsia, suggests that aspirin may be an effective prophylaxis. Further research will be necessary: measuring the expression of tissue factor on monocytes using flowcytometry and comparing the development of this expression during normal pregnancy and pregnancy complicated by preeclampsia, for example. Another possibility is immunohistochemical determination of the level of TF expression directly in placental tissue.

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“…estrogen, in cigarette smokers and in hyperhomocysteinemia [32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] .…”

Section: Inflammationmentioning

confidence: 99%

The role of tissue factor in normal pregnancy and in the development of preeclampsia: A review

Procházková¹,

Slavík²,

Úlehlová³

et al. 2015

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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“…It was also shown previously that simvastatin reduced TF expression and activity in blood monocytes in patients with nephritic syndrome (18). Other statins also suppress TF expression in various cell types (19,20). Knowing that TF is a crucial mediator in aPL-induced pregnancy loss and that statins diminish TF expression, we sought to determine whether statins can prevent pregnancy loss in aPL-IgG-treated mice.…”

Section: Increased Synthesis Of Tf and Par2 In Neutrophils From Apl-imentioning

confidence: 99%

Neutrophil activation by the tissue factor/Factor VIIa/PAR2 axis mediates fetal death in a mouse model of antiphospholipid syndrome

Redecha¹,

Franzke²,

Ruf³

et al. 2008

J. Clin. Invest.

116

174

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Women with antiphospholipid syndrome (APS), a condition characterized by the presence of antiphospholipid antibodies (aPL), often suffer pregnancy-related complications, including miscarriage. We have previously shown that C5a induction of tissue factor (TF) expression in neutrophils contributes to respiratory burst, trophoblast injury, and pregnancy loss in mice treated with aPL. Here we analyzed how TF contributes to neutrophil activation and trophoblast injury in this model. Neutrophils from aPL-treated mice expressed protease-activated receptor 2 (PAR2), and stimulation of this receptor led to neutrophil activation, trophoblast injury, and fetal death. An antibody specific for human TF that has little impact on coagulation, but potently inhibits TF/Factor VIIa (FVIIa) signaling through PAR2, inhibited aPL-induced neutrophil activation in mice that expressed human TF. Genetic deletion of the TF cytoplasmic domain, which allows interaction between TF and PAR2, reduced aPL-induced neutrophil activation in aPL-treated mice. Par2 -/-mice treated with aPL exhibited reduced neutrophil activation and normal pregnancies, which indicates that PAR2 plays an important role in the pathogenesis of aPL-induced fetal injury. We also demonstrated that simvastatin and pravastatin decreased TF and PAR2 expression on neutrophils and prevented pregnancy loss. Our results suggest that TF/FVIIa/PAR2 signaling mediates neutrophil activation and fetal death in APS and that statins may be a good treatment for women with aPL-induced pregnancy complications.

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“…One of the key steps in the thrombin-induced TF activity is the binding hydrophobic groups consisting of geranylgeranyl residues to the carboxyl terminal of Rho protein (Kunieda et al 2003). In this regard, Fig.…”

Section: Resultsmentioning

confidence: 99%

Atorvastatin neutralises the thrombin-induced tissue factor expresion in endothelial cells via geranylgeranyl pyrophosphate

et al. 2010

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Statins may have beneficial effects in atherogenesis given their antithrombotic properties involving non-lipid mechanisms that modify endothelial function of tissue factor induction by thrombin. In this study, we investigate the effect of atorvastatin on tissue factor (TF) activity in thrombin-stimulated endothelial cells and its regulation through mevalonate or its derivatives. First subculture of human umbilical endothelial cells was used for this study. Cells were treated with thrombin and atorvastatin for different time intervals and dosage. Tissue factor activity was measured as Factor Xa generation induced by Tissue Factor-Factor VIIa complex on confluent cells. Our results show that atorvastatin prevents the thrombin-induced up-regulation of tissue factor activity in a concentrationdependent manner. Mevalonate and geranylgeranyl pyrophosphate reversed this inhibitory effect of atorvastatin on tissue factor activity, while the presence of farnesyl pyrophosphate did not prevent the atorvastatin effect on thrombin-induced tissue factor activity. Rho-kinase inhibitor did not affect the thrombin stimulation of tissue factor activity. High amount of hydrophobic isoprenoid groups decreases the thrombin-induced TF activity and may promote endothelial cell anti-thrombotic action. Rho kinase pathways do not have a major role in the thrombinmediated TF activity. The inhibitory effect of atorvastatin on thrombin-induced TF activity was partially reversed by MVA and GGPP but not FPP.

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HMG CoA reductase inhibitor suppresses the expression of tissue factor and plasminogen activator inhibitor-1 induced by angiotensin II in cultured rat aortic endothelial cells

Cited by 46 publications

References 26 publications

The role of tissue factor in normal pregnancy and in the development of preeclampsia: A review

The role of tissue factor in normal pregnancy and in the development of preeclampsia: A review

Neutrophil activation by the tissue factor/Factor VIIa/PAR2 axis mediates fetal death in a mouse model of antiphospholipid syndrome

Atorvastatin neutralises the thrombin-induced tissue factor expresion in endothelial cells via geranylgeranyl pyrophosphate

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