Factor Xa inhibits HMGB1-induced septic responses in human umbilical vein endothelial cells and in mice

Wonhwa Lee; Sae-Kwang Ku; Jong-Sup Bae

doi:10.1160/TH14-03-0233

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2014; 112(04): 757-769
DOI: 10.1160/TH14-03-0233

Wound Healing and Inflammation/Infection

Schattauer GmbH

Factor Xa inhibits HMGB1-induced septic responses in human umbilical vein endothelial cells and in mice

Wonhwa Lee^*

¹College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea

²Department of Biochemistry and Cell Biology, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu, Republic of Korea

,

Sae-Kwang Ku^*

³Department of Anatomy and Histology, College of Korean Medicine, Daegu Haany University, Gyeongsan, Republic of Korea

,

Jong-Sup Bae

¹College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea

› Author Affiliations

Abstract

Summary

Nuclear DNA-binding protein high mobility group box 1 (HMGB1) acts as a late mediator of severe vascular inflammatory conditions, such as sepsis. Activated factor X (FXa) is an important player in the coagulation cascade responsible for thrombin generation, and it influences cell signalling in various cell types by activating protease-activated receptors (PARs). However, the effect of FXa on HMGB1-induced inflammatory response has not been studied. First, we addressed this issue by monitoring the effects of post-treatment with FXa on lipopolysaccharide (LPS)- and cecal ligation and puncture (CLP)-mediated release of HMGB1 and HMGB1-mediated regulation of pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs) and septic mice. Post-treatment with FXa was found to suppress LPS-mediated release of HMGB1 and HMGB1-mediated cytoskeletal rearrangements. FXa also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in septic mice. In addition, FXa inhibited the production of tumour necrosis factor-α and interleukin (IL)-1β. FXa also facilitated the downregulation of CLP-induced release of HMGB1, production of IL-6, and mortality. Collectively, these results suggest that FXa may be regarded as a candidate therapeutic agent for treating vascular inflammatory diseases by inhibiting the HMGB1 signalling pathway.

Keywords

FXa - HMGB1 - vascular inflammation - sepsis

Full Text

References

References
1 Lotze MT, Tracey KJ. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nature Rev Immunol 2005; 5: 331-342.
2 Bianchi ME, Manfredi A. Chromatin and cell death. Biochim Biophys Acta 2004; 1677: 181-186.
3 Degryse B, Bonaldi T, Scaffidi P. et al. The high mobility group (HMG) boxes of the nuclear protein HMG1 induce chaemotaxis and cytoskeleton reorganisation in rat smooth muscle cells. J Cell Biol 2001; 152: 1197-1206.
4 Ito I, Fukazawa J, Yoshida M. Post-translational methylation of high mobility group box 1 (HMGB1) causes its cytoplasmic localisation in neutrophils. J Biol Chem 2007; 282: 16336-16344.
5 Andersson U, Tracey KJ. HMGB1 is a therapeutic target for sterile inflammation and infection. Ann Rev Immunol 2011; 29: 139-162.
6 Hori O, Brett J, Slattery T. et al. The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J Biol Chem 1995; 270: 25752-25761.
7 Park JS, Svetkauskaite D, He Q. et al. Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem 2004; 279: 7370-7377.
8 Yang H, Ochani M, Li J. et al. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc Natl Acad Sci USA 2004; 101: 296-301.
9 Dahlback B. Blood coagulation. Lancet 2000; 355: 1627-1632.
10 Steinberg SF. The cardiovascular actions of protease-activated receptors. Mol Pharmacol 2005; 67: 2-11.
11 Ossovskaya VS, Bunnett NW. Protease-activated receptors: contribution to physiology and disease. Physiol Rev 2004; 84: 579-621.
12 Bohm SK, Kong W, Bromme D. et al. Molecular cloning, expression and potential functions of the human proteinase-activated receptor-2. Biochem J 1996; 314: 1009-1016.
13 Shapiro MJ, Weiss EJ, Faruqi TR. et al. Protease-activated receptors 1 and 4 are shut off with distinct kinetics after activation by thrombin. J Biol Chem 2000; 275: 25216-25221.
14 Macfarlane SR, Seatter MJ, Kanke T. et al. Proteinase-activated receptors. Pharmacol Rev 2001; 53: 245-282.
15 Bae JS. Role of high mobility group box 1 in inflammatory disease: Focus on sepsis. Arch Pharm Res 2012; 35: 1511-1523.
16 Angus DC, Yang L, Kong L. et al. Circulating high-mobility group box 1 (HMGB1) concentrations are elevated in both uncomplicated pneumonia and pneumonia with severe sepsis. Crit Care Med 2007; 35: 1061-1067.
17 Wang H, Zhu S, Zhou R. et al. Therapeutic potential of HMGB1-targeting agents in sepsis. Expert Rev Mol Med 2008; 10: e32.
18 Bae JS, Rezaie AR. Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand. Thromb Haemost 2008; 100: 101-109.
19 Lee W, Yang EJ, Ku SK. et al. Anticoagulant activities of oleanolic acid via inhibition of tissue factor expressions. BMB Rep 2012; 45: 390-395.
20 Kim TH, Bae JS. Ecklonia cava extracts inhibit lipopolysaccharide induced inflammatory responses in human endothelial cells. Food Chem Toxicol 2010; 48: 1682-1687.
21 Lee W, Kim TH, Ku SK. et al. Barrier protective effects of withaferin A in HMGB1-induced inflammatory responses in both cellular and animal models. Toxicol Appl Pharmacol 2012; 262: 91-98.
22 Wang H, Liao H, Ochani M. et al. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med 2004; 10: 1216-1221.
23 Bae JS, Rezaie AR. Activated protein C inhibits high mobility group box 1 signalling in endothelial cells. Blood 2011; 118: 3952-3959.
24 Lee JD, Huh JE, Jeon G. et al. Flavonol-rich RVHxR from Rhus verniciflua Stokes and its major compound fisetin inhibits inflammation-related cytokines and angiogenic factor in rheumatoid arthritic fibroblast-like synovial cells and in vivo models. Int Immunopharmacol 2009; 9: 268-276.
25 Bae JS, Lee W, Rezaie AR. Polyphosphate elicits pro-inflammatory responses that are counteracted by activated protein C in both cellular and animal models. J Thromb Haemost 2012; 10: 1145-1151.
26 Valerio DA, Cunha TM, Arakawa NS. et al. Anti-inflammatory and analgesic effects of the sesquiterpene lactone budlein A in mice: inhibition of cytokine production-dependent mechanism. Eur J Pharmacol 2007; 562: 155-163.
27 Che W, Lerner-Marmarosh N, Huang Q. et al. Insulin-like growth factor-1 enhances inflammatory responses in endothelial cells: role of Gab1 and MEKK3 in TNF-alpha-induced c-Jun and NF-kappaB activation and adhesion molecule expression. Circ Res 2002; 90: 1222-1230.
28 Kim TH, Ku SK, Lee IC. et al. Anti-inflammatory functions of purpurogallin in LPS-activated human endothelial cells. BMB Rep 2012; 45: 200-205.
29 Akeson AL, Woods CW. A fluorometric assay for the quantitation of cell adherence to endothelial cells. J Immunol Methods 1993; 163: 181-185.
30 Ozdulger A, Cinel I, Koksel O. et al. The protective effect of N-acetylcysteine on apoptotic lung injury in cecal ligation and puncture-induced sepsis model. Shock 2003; 19: 366-372.
31 Dejana E, Callioni A, Quintana A. et al. Bleeding time in laboratory animals. II -A comparison of different assay conditions in rats. Thromb Res 1979; 15: 191-197.
32 Kim TH, Ku SK, Bae JS. Antithrombotic and profibrinolytic activities of eckol and dieckol. J Cell Biochem 2012; 113: 2877-2883.
33 Kim DC, Ku SK, Bae JS. Anticoagulant activities of curcumin and its derivative. BMB Rep 2012; 45: 221-226.
34 Mullins GE, Sunden-Cullberg J, Johansson AS. et al. Activation of human umbilical vein endothelial cells leads to relocation and release of high-mobility group box chromosomal protein 1. Scand J Immunol 2004; 60: 566-573.
35 Mann KG, Nesheim ME, Church WR. et al. Surface-dependent reactions of the vitamin K-dependent enzyme complexes. Blood 1990; 76: 1-16.
36 Buras JA, Holzmann B, Sitkovsky M. Animal models of sepsis: setting the stage. Nature Rev Drug Discov 2005; 4: 854-865.
37 Bonaldi T, Talamo F, Scaffidi P. et al. Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J 2003; 22: 5551-5560.
38 Ito T, Kawahara K, Okamoto K. et al. Proteolytic cleavage of high mobility group box 1 protein by thrombin-thrombomodulin complexes. Arterioscler Thromb Vasc Biol 2008; 28: 1825-1830.
39 Berman RS, Frew JD, Martin W. Endotoxin-induced arterial endothelial barrier dysfunction assessed by an in vitro model. Br J Pharmacol 1993; 110: 1282-1284.
40 Goldblum SE, Ding X, Brann TW. et al. Bacterial lipopolysaccharide induces actin reorganisation, intercellular gap formation, and endothelial barrier dysfunction in pulmonary vascular endothelial cells: concurrent F-actin depolymerisation and new actin synthesis. J Cell Physiol 1993; 157: 13-23.
41 Yang H, Wang H, Czura CJ. et al. The cytokine activity of HMGB1. J Leukoc Biol 2005; 78: 1-8.
42 Schnittler HJ, Schneider SW, Raifer H. et al. Role of actin filaments in endothelial cell-cell adhesion and membrane stability under fluid shear stress. Pflugers Arch Eur J Physiol 2001; 442: 675-687.
43 Friedl J, Puhlmann M, Bartlett DL. et al. Induction of permeability across endothelial cell monolayers by tumor necrosis factor (TNF) occurs via a tissue factor-dependent mechanism: relationship between the procoagulant and permeability effects of TNF. Blood 2002; 100: 1334-1339.
44 Petrache I, Birukova A, Ramirez SI. et al. The role of the microtubules in tumor necrosis factor-alpha-induced endothelial cell permeability. Am J Resp C Mol Biol 2003; 28: 574-581.
45 Andersson U, Wang H, Palmblad K. et al. High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J Exp Med 2000; 192: 565-570.
46 Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nature Rev Immunol 2006; 6: 508-519.
47 Wang FP, Li L, Li J. et al. High Mobility Group Box-1 Promotes the Proliferation and Migration of Hepatic Stellate Cells via TLR4-Dependent Signal Pathways of PI3K/Akt and JNK. PloS one 2013; 8: e64373.
48 Lockyer JM, Colladay JS, Alperin-Lea WL. et al. Inhibition of nuclear factor-kappaB-mediated adhesion molecule expression in human endothelial cells. Circulation Res 1998; 82: 314-320.
49 Rose BA, Force T, Wang Y. Mitogen-activated protein kinase signalling in the heart: angels versus demons in a heart-breaking tale. Physiol Rev 2010; 90: 1507-1546.
50 Park JS, Gamboni-Robertson F, He Q. et al. High mobility group box 1 protein interacts with multiple Toll-like receptors. Am J Physiol Cell Physiol 2006; 290: C917-924.
51 Yang H, Tracey KJ. Targeting HMGB1 in inflammation. Biochim Biophys Acta 2010; 1799: 149-156.
52 Erlandsson Harris H, Andersson U. Mini-review: The nuclear protein HMGB1 as a proinflammatory mediator. Eur J Immunol 2004; 34: 1503-1512.
53 Cohen J. The immunopathogenesis of sepsis. Nature 2002; 420: 885-891.
54 Teiten MH, Eifes S, Dicato M. et al. Curcumin-the paradigm of a multi-target natural compound with applications in cancer prevention and treatment. Toxins 2010; 2: 128-162.
55 Xiao H, Siddiqui J, Remick DG. Mechanisms of mortality in early and late sepsis. Infect Immun 2006; 74: 5227-5235.
56 Bhatia M, He M, Zhang H. et al. Sepsis as a model of SIRS. Front Biosci 2009; 14: 4703-4711.
57 Tracey KJ, Fong Y, Hesse DG. et al. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 1987; 330: 662-664.
58 Wichterman KA, Baue AE, Chaudry IH. Sepsis and septic shock--a review of laboratory models and a proposal. J Surg Res 1980; 29: 189-201.
59 Wang H, Yang H, Czura CJ. et al. HMGB1 as a late mediator of lethal systemic inflammation. Am J Respir Crit Care Med 2001; 164: 1768-1773.
60 Nooteboom A, Hendriks T, Otteholler I. et al. Permeability characteristics of human endothelial monolayers seeded on different extracellular matrix proteins. Mediators Inflam 2000; 9: 235-241.
61 Aird WC. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 2003; 101: 3765-3777.
62 Bogatcheva NV, Verin AD. The role of cytoskeleton in the regulation of vascular endothelial barrier function. Microvasc Res 2008; 76: 202-207.
63 Fiuza C, Bustin M, Talwar S. et al. Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. Blood 2003; 101: 2652-2660.
64 Sama AE, D‘Amore J, Ward MF. et al. Bench to bedside: HMGB1-a novel proinflammatory cytokine and potential therapeutic target for septic patients in the emergency department. Acad Emerg Med 2004; 11: 867-873.
65 Chen G, Ward MF, Sama AE. et al. Extracellular HMGB1 as a proinflammatory cytokine. J Interferon Cytokine Res 2004; 24: 329-333.
66 Wang H, Bloom O, Zhang M. et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science 1999; 285: 248-251.