TAK-442, a Direct Factor Xa Inhibitor, Inhibits Monocyte Chemoattractant Protein 1 Production in Endothelial Cells via Involvement of Protease-Activated Receptor 1

Shinozawa, Emiko; Nakayama, Masaharu; Imura, Yoshimi

doi:10.3389/fphar.2018.01431

Cited by 9 publications

(7 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As shown in Figure A,B, P-2-CG (0.1 mM) and thrombin (1 U) had no discernible influence on HUVECs viability ( p > 0.05). This finding was consistent with previous results. − The disrupted ECs also expressed a variety of physiological/pathological factors (such as ROS, cytokines, and vWF). , Furthermore, these factors trigger platelet aggregation and induce thrombosis further. Exposure of HUVECs to thrombin resulted in an enhanced release of inflammatory molecule IL-6 (Figure C) and prothrombotic agent vWF (Figure D).…”

Section: Resultssupporting

confidence: 93%

Crassostrea gigas-Based Bioactive Peptide Protected Thrombin-Treated Endothelial Cells against Thrombosis and Cell Barrier Dysfunction

Cheng

Yuan

et al. 2022

J. Agric. Food Chem.

View full text Add to dashboard Cite

The activation of thrombin-treated endothelial cells resulted in disruption of the vascular tissues. A novel oyster-derived bioactive dodecapeptide (IEELEELEAER, P-2-CG) was reported to protect the human umbilical vein endothelial cells and their barrier function via the decrease of VE-cadherin disruption and the restoration of the F-actin arrangement. The promotion of the extrinsic pathway in this case triggers the release of tissue factors that occurs on the surface of the endothelial cells, thus changing the antithrombotic to prothrombotic. P-2-CG induced accordingly a prolongation of plasma clotting time and thrombin generation time, following the alteration of the antithrombotic phenotype. Furthermore, the antithrombotic activity of P-2-CG was also supported by the reduction of FXa and the inhibition of other factors release, for instance, inflammation factors, ROS, etc. In addition to its antithrombogenic role, P-2-CG displayed anti-inflammatory and antioxidant properties via the mitogen-activated protein kinase cascades and central signaling pathways as shown in an in vitro model of endothelial dysfunction.

show abstract

Section: Resultssupporting

confidence: 93%

Crassostrea gigas-Based Bioactive Peptide Protected Thrombin-Treated Endothelial Cells against Thrombosis and Cell Barrier Dysfunction

Cheng

Yuan

et al. 2022

J. Agric. Food Chem.

View full text Add to dashboard Cite

show abstract

“…In fact, FXa was found to stimulate proinflammatory and profibrotic responses in fibroblasts [58], human atrial tissue [59], and RAW 264.7 macrophages [60] via protease-activated receptor-2. An investigational FXa inhibitor was also recently reported to inhibit MCP-1 production in endothelial cells via protease-activated receptor-1 [61]. As a result, FXa-mediated signaling has been implicated in the pathogenesis of several inflammatory diseases, including fibrosis, cardiovascular diseases, diabetic nephropathy, and cancer [62,63].…”

Section: Anti-inflammatory Activity Of Direct Fxa Inhibitorsmentioning

confidence: 99%

Potential Therapeutic Roles for Direct Factor Xa Inhibitors in Coronavirus Infections

Al‐Horani

2020

Am J Cardiovasc Drugs

View full text Add to dashboard Cite

Human factor Xa (FXa) is a serine protease of the common coagulation pathway. FXa is known to activate prothrombin to thrombin, which eventually leads to the formation of cross-linked blood clots. While this process is important in maintaining hemostasis, excessive thrombin generation results in a host of thrombotic conditions. FXa has also been linked to inflammation via protease-activated receptors. Together, coagulopathy and inflammation have been implicated in the pathogenesis of viral infections, including the current coronavirus pandemic. Direct FXa inhibitors have been shown to possess anti-inflammatory and antiviral effects, in addition to their established anticoagulant activity. This review summarizes the pharmacological activities of direct FXa inhibitors, their pharmacokinetics, potential drug-drug interactions and adverse effects, and the details of clinical trials involving direct FXa inhibitors in coronavirus disease 2019 (COVID-19) patients. Key Points Factor Xa is a serine protease in the common coagulation pathway, the excessive stimulation of which leads to a host of thrombotic conditions. Factor Xa has also been linked to inflammation as well as viral infections. In addition to their established anticoagulant properties, factor Xa inhibitors have exhibited significant anti-inflammatory and antiviral effects in several testing settings. Currently, there are > 10 clinical trials for evaluating the potential of factor Xa inhibitors in coronavirus disease 2019 (COVID-19) patients. Strategies to administer these drugs parenterally may facilitate their use in critically ill COVID-19 patients.

show abstract

“…Thus, PAR1 has been shown to be expressed in activated ECs of atherosclerotic plaque, but not in non-diseased cardiac arteries [ 15 , 16 , 41 ]. Previous studies demonstrated that vorapaxar prevented endothelial barrier disruption in cultured ECs [ 42 , 43 , 44 , 45 ]. Here, we report that vorapaxar reduced the expression of inflammation-associated adhesion molecules and TF, both in isolated ECs and the aorta in a murine model of atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Pleiotropic Effects of the Protease-Activated Receptor 1 (PAR1) Inhibitor, Vorapaxar, on Atherosclerosis and Vascular Inflammation

Friebel

Moritz

Witkowski

et al. 2021

Cells

View full text Add to dashboard Cite

Background: Protease-activated receptor 1 (PAR1) and toll-like receptors (TLRs) are inflammatory mediators contributing to atherogenesis and atherothrombosis. Vorapaxar, which selectively antagonizes PAR1-signaling, is an approved, add-on antiplatelet therapy for secondary prevention. The non-hemostatic, platelet-independent, pleiotropic effects of vorapaxar have not yet been studied. Methods and Results: Cellular targets of PAR1 signaling in the vasculature were identified in three patient cohorts with atherosclerotic disease. Evaluation of plasma biomarkers (n = 190) and gene expression in endomyocardial biopsies (EMBs) (n = 12) revealed that PAR1 expression correlated with endothelial activation and vascular inflammation. PAR1 colocalized with TLR2/4 in human carotid plaques and was associated with TLR2/4 gene transcription in EMBs. In addition, vorapaxar reduced atherosclerotic lesion size in apolipoprotein E–knock out (ApoEko) mice. This reduction was associated with reduced expression of vascular adhesion molecules and TLR2/4 presence, both in isolated murine endothelial cells and the aorta. Thrombin-induced uptake of oxLDL was augmented by additional TLR2/4 stimulation and abrogated by vorapaxar. Plaque-infiltrating pro-inflammatory cells were reduced in vorapaxar-treated ApoEko mice. A shift toward M2 macrophages paralleled a decreased transcription of pro-inflammatory cytokines and chemokines. Conclusions: PAR1 inhibition with vorapaxar may be effective in reducing residual thrombo-inflammatory event risk in patients with atherosclerosis independent of its effect on platelets.

show abstract

TAK-442, a Direct Factor Xa Inhibitor, Inhibits Monocyte Chemoattractant Protein 1 Production in Endothelial Cells via Involvement of Protease-Activated Receptor 1

Cited by 9 publications

References 26 publications

Crassostrea gigas-Based Bioactive Peptide Protected Thrombin-Treated Endothelial Cells against Thrombosis and Cell Barrier Dysfunction

Crassostrea gigas-Based Bioactive Peptide Protected Thrombin-Treated Endothelial Cells against Thrombosis and Cell Barrier Dysfunction

Potential Therapeutic Roles for Direct Factor Xa Inhibitors in Coronavirus Infections

Pleiotropic Effects of the Protease-Activated Receptor 1 (PAR1) Inhibitor, Vorapaxar, on Atherosclerosis and Vascular Inflammation

Contact Info

Product

Resources

About