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

被引:9
作者
Shinozawa, Emiko [1 ]
Nakayama, Masaharu [1 ]
Imura, Yoshimi [1 ]
机构
[1] Takeda Pharmaceut Co Ltd, Res, Fujisawa, Kanagawa, Japan
来源
FRONTIERS IN PHARMACOLOGY | 2018年 / 9卷
关键词
factor Xa; thrombin; monocyte chemoattractant protein 1; endothelial cells; protease-activated receptor 1; COAGULATION-FACTOR-XA; THROMBIN INHIBITOR; INFLAMMATION; RIVAROXABAN; POTENT;
D O I
10.3389/fphar.2018.01431
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Oral blood coagulation inhibitors and their receptors, such as factor Xa (FXa), thrombin, and the thrombin receptor protease-activated receptor 1 (PAR1), are entered into clinical trials for acute coronary syndrome therapy; however, the results obtained so far are different for each drug. The underlying mechanisms of the results have not been fully investigated. We studied the in vitro anti-inflammatory effects of the selective FXa inhibitor TAK-442 on human endothelial cells, with comparing those of the selective thrombin inhibitor melagatran and the PAR1 antagonist vorapaxar. In human umbilical vein endothelial cells, FXa-increased production of monocyte chemoattractant protein 1 (MCP-1), a key inflammatory mediator, was inhibited by TAK-442 but not melagatran, and was also remarkably suppressed by vorapaxar. As thrombin did, FXa increased calcium mobilization in PAR1-overexpressed Chinese hamster ovary cells, which was selectively inhibited by TAK-442 and vorapaxar. We therefore confirmed the inhibitory effect of TAK-442 in endothelial MCP-1 production and the PAR1 intervention in the response. Our results suggest that TAK-442 may have anti-inflammatory potential in addition to its anti-thrombotic effects.
引用
收藏
页数:6
相关论文
共 26 条
  • [1] ALTIERI DC, 1994, J BIOL CHEM, V269, P3139
  • [2] Coagulation factor Xa stimulates interleukin-8 release in endothelial cells and mononuclear leukocytes -: Implications in acute myocardial infarction
    Busch, G
    Seitz, I
    Steppich, B
    Hess, S
    Eckl, R
    Schömig, A
    Ott, I
    [J]. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2005, 25 (02) : 461 - 466
  • [3] Genetic evidence that protease-activated receptors mediate factor Xa signaling in endothelial cells
    Camerer, E
    Kataoka, H
    Kahn, M
    Lease, K
    Coughlin, SR
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (18) : 16081 - 16087
  • [4] Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity
    Chackalamannil, Samuel
    Wang, Yuguang
    Greenlee, William J.
    Hu, Zhiyong
    Xia, Yan
    Ahn, Ho-Sam
    Boykow, George
    Hsieh, Yunsheng
    Palamanda, Jairam
    Agans-Fantuzzi, Jacqueline
    Kurowski, Stan
    Graziano, Michael
    Chintala, Madhu
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (11) : 3061 - 3064
  • [5] Factor Xa and thrombin evoke additive calcium and proinflammatory responses in endothelial cells subjected to coagulation
    Daubie, Valery
    Cauwenberghs, Sandra
    Senden, Nicole H. M.
    Pochet, Roland
    Lindhout, Theo
    Buurman, Wim A.
    Heemskerk, Johan W. M.
    [J]. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, 2006, 1763 (08): : 860 - 869
  • [6] PAR1 agonists stimulate APC-like endothelial cytoprotection and confer resistance to thromboinflammatory injury
    De Ceunynck, Karen
    Peters, Christian G.
    Jain, Abhishek
    Higgins, Sarah J.
    Aisiku, Omozuanvbo
    Fitch-Tewfik, Jennifer L.
    Chaudhry, Sharjeel A.
    Dockendorff, Chris
    Parikh, Samir M.
    Ingber, Donald E.
    Flaumenhaft, Robert
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2018, 115 (05) : E982 - E991
  • [7] Expression of pro-inflammatory genes in human endothelial cells: Comparison of rivaroxaban and dabigatran
    Ellinghaus, Peter
    Perzborn, Elisabeth
    Hauenschild, Peter
    Gerdes, Christoph
    Heitmeier, Stefan
    Visser, Mayken
    Summer, Holger
    Laux, Volker
    [J]. THROMBOSIS RESEARCH, 2016, 142 : 44 - 51
  • [8] Protease-activated receptors-1 and-2 can mediate endothelial barrier protection: role in factor Xa signaling
    Feistritzer, C
    Lenta, R
    Riewald, M
    [J]. JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 2005, 3 (12) : 2798 - 2805
  • [9] Discovery of a Tetrahydropyrimidin-2(1H)-one Derivative (TAK-442) as a Potent, Selective, and Orally Active Factor Xa Inhibitor
    Fujimoto, Takuya
    Imaeda, Yasuhiro
    Konishi, Noriko
    Hiroe, Katsuhiko
    Kawamura, Masaki
    Textor, Garret P.
    Aertgeerts, Kathleen
    Kubo, Keiji
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2010, 53 (09) : 3517 - 3531
  • [10] MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions
    Gerszten, RE
    Garcia-Zepeda, EA
    Lim, YC
    Yoshida, M
    Ding, HA
    Gimbrone, MA
    Luster, AD
    Luscinskas, FW
    Rosenzweig, A
    [J]. NATURE, 1999, 398 (6729) : 718 - 723