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DOI: 10.1160/TH05-06-0415
Thrombomodulin plays an important role in arterial remodeling and neointima formation in mouse carotid ligation model
Financial support: This work was supported by grant 92–2314-B-006–131, 93–2314-B-006–094 from the National Science Council, Taipei, Taiwan, and 91-B-FA09–2–4 from the Ministry of Education Program for Promoting Academic Excellence of Universities, Taipei, Taiwan.Publikationsverlauf
Received
14. Juni 2005
Accepted after resubmission
11. November 2005
Publikationsdatum:
28. November 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/200601/lookinside/thumbnails/10-1160-th05-06-0415-1.jpg)
Summary
Thrombomodulin (TM) is a cell membrane-bound glycoprotein that functions as a thrombin cofactor in the activation of protein C. Its protein structure includes a N-terminal lectin-like domain (D1), 6 epidermal growth factor repeats (D2), a serine-threonine-rich region (D3), a transmembrane domain (D4) and a short cytoplasmic tail (D5). Recent studies have demonstrated the direct effect ofTM on cellular proliferation, adhesion and inflammation. In the study, we investigated the role of TM in vascular remodeling and neointima formation in a mouse carotid ligation model. TM expressions on the endothelium, neointima and media were examined in the ligated carotid artery by immunohistochemistry and quantitative real-time reverse transcription PCR. Endothelial TM expression decreased after ligation and appeared later in the media and neointima, which is quite similar to the appearance of TM in the human atherosclerotic process. Recombinant TMD123 was prepared. It was effective for thrombin-dependent protein C activation and the inhibition of leukocyte adhesion to the vessel wall after carotid ligation. RecombinantTMD123 and saline was administered immediately before and after carotid ligation. The TM-treated arteries demonstrated significantly less arterial dilatation (30279±12605 vs 73789±15073 µm2, p<0.05) in response to less neointima formation (14179±6538 vs 42227±8754 µm2, p<0.05) at 4 weeks after ligation. Our data indicated that there was a compensatory increase inTM expression in the media and neointima in relation to the reduced endothelial TM after carotid ligation. Early recombinant TM treatment in mice undergoing carotid ligation altered vascular remodeling and decreased the severity of neointima formation.
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References
- 1 Esmon CT. The regulation of natural anticoagulant pathways. Science 1987; 235: 1348-52.
- 2 Esmon CT. The roles of protein C and thrombomodulin in the regulation of blood coagulation. J Biol Chem 1989; 264: 4743-6.
- 3 Wen D, Dittman WA, Ye RD. et al. Human thrombomodulin: complete cDNA sequence and chromosome localization of the gene. Biochemistry 1987; 26: 4350-7.
- 4 Kurosawa S, Stearns DJ, Jackson KW. et al. A 10-kDa cyanogen bromide fragment from the epidermal growth factor homology domain of rabbit thrombomodulin contains the primary thrombin binding site. J Biol Chem 1988; 263: 5993-6.
- 5 Stearns DJ, Kurosawa S, Esmon CT. Microthrombomodulin. Residues 310–486 from the epidermal growth factor precursor homology domain of thrombomodulin will accelerate protein C activation. J Biol Chem 1988; 264: 3352-6.
- 6 Li J, Garnette CS, Cahn M. et al. Recombinant thrombomodulin inhibits arterial smooth muscle cell proliferation induced by thrombin. J Vasc Surg 2000; 32: 804-13.
- 7 Tohda G, Oida K, Okada Y. et al Expression of thrombomodulin in atherosclerotic lesions and mitogenic activity of recombinant thrombomodulin in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 1998; 18: 1861-9.
- 8 Shi CS, Shi GY, Chang YS. et al. Evidence of human thrombomodulin domain as a novel angiogenic factor. Circulation 2005; 111: 1627-36.
- 9 Huang HC, Shi GY, Jiang SJ. et al. Thrombomodulin-mediated cell adhesion. J Biol Chem 2003; 278: 46750-9.
- 10 Conway EM, Van de Wouwer M, Pollefeyt S. et al. The lectin-like domain of thrombomodulin confers protection from neutrophil-mediated tissue damage by suppressing adhesion molecule expression via nuclear factor kB and mitogen-activated protein kinase pathways. J Exp Med 2002; 196: 565-77.
- 11 Li YH, Chen JH, Wu HL. et al. G-33A mutation in the promoter region of thrombomodulin gene and its association with coronary artery disease and plasma soluble thrombomodulin levels. Am J Cardiol 2000; 85: 8-12.
- 12 Li YH, Chen CH, Yeh PS. et al. Functional mutation in the promoter region of thrombomodulin gene in relation to carotid atherosclerosis. Atherosclerosis 2001; 154: 713-9.
- 13 Yoshii Y, Okada Y, Sasaki S. et al. Expression of thrombomodulin in human aortic smooth muscle cells with special reference to atherosclerotic lesion types and age differences. Med Electron Microsc 2003; 36: 165-72.
- 14 Kumar A, Lindner V. Remodeling with neointima formation in the mouse carotid artery after cessation of blood flow. Arterioscler Thromb Vasc Biol 1997; 17: 2238-44.
- 15 Li J, Singh MJ, Itani M. et al. Recombinant human thrombomodulin inhibits arterial neointimal hyperplasia after balloon injury. J Vasc Surg 2004; 39: 1074-83.
- 16 Myers DL, Liaw L. Improved analysis of the vascular response to arterial ligation using a multivariate approach. Am J Pathol 2004; 164: 43-8.
- 17 Kumar A, Hoover JL, Simmons CA. et al. Remodeling and neointima formation in the carotid artery of normal and p-selectin-deficient mice. Circulation 1997; 96: 4333-42.
- 18 Faust SN, Levin M, Harrison OB. et al. Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N Engl J Med 2001; 345: 408-16.
- 19 Conway EM, Rosenberg RD. Tumor necrosis factor suppresses transcription of the thrombomodulin gene in endothelial cells. Mol Cell Biol 1988; 08: 5588-92.
- 20 Nawroth PP, Handley DA, Esmon CT. et al. Interleukin 1 induces endothelial cell procoagulant while suppressing cell-surface anticoagulant activity. Proc Natl Acad Sci U S A 1986; 83: 3460-4.
- 21 Boehme MW, Deng Y, Raeth U. et al. Release of thrombomodulin from endothelial cells by concerted action of TNF-alpha and neutrophils: in vivo and in vitro studies. Immunology 1996; 87: 134-40.
- 22 Laszik ZG, Zhou XJ, Ferrell GL. et al. Down-regulation of endothelial expression of endothelial cell protein C receptor and thrombomodulin in coronary atherosclerosis. Am J Pathol 2001; 159: 797-802.
- 23 Grinnell BW, Berg DT. Surface thrombomodulin modulates thrombin receptor responses on vascular smooth muscle cells. Am J Physio 1996; 270: H603-H609.
- 24 Moll S, Lindley C, Pescatore S. et al. Phase I study of a novel recombinant human soluble thrombomodulin, ART-123. J Thromb Haemost 2004; 02: 1745-51.
- 25 Aoki Y, Takei R, Mohri M. et al. Antithrombotic effects of recombinant human soluble thrombomodulin (rhs-TM) on arteriovenous shunt thrombosis in rats. Am J Hematol 1994; 47: 162-6.
- 26 Mohri M, Gonda Y, Oka M. et al. The antithrombotic effects of recombinant human thrombomodulin (rhsTM) on tissue factor-induced disseminated intravascular coagulation in crab-eating monkeys (Macaca fascicularis). Blood Coagul Fibrinolysis 1997; 08: 274-83.
- 27 Riewald M, Petrovan RJ, Donner A. et al. Activation of endothelial cell protease activated receptor1 by the protein C pathway. Science 2002; 296: 1880-2.
- 28 Abeyama K, Stern DM, Ito Y. et al. The N-terminal domain of thrombomodulin sequesters high-mobolity-B1 protein, a novel antiinflammatory mechanism. J Clin Invest 2005; 115: 1267-74.
- 29 Sakaguchi T, Yan SF, Yan SD. et al. Central role of RAGE-dependent neointimal expansion in arterial restenosis. J Clin Invest 2003; 111: 959-72.