ADAM15 is an adhesion receptor for platelet GPIIb-IIIa and induces platelet activation

Harald Langer; Andreas E. May; Andreas Bültmann; Meinrad Gawaz

doi:10.1160/TH04-12-0784

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2005; 94(03): 555-561
DOI: 10.1160/TH04-12-0784

Platelets and Blood Cells

Schattauer GmbH

ADAM15 is an adhesion receptor for platelet GPIIb-IIIa and induces platelet activation

Authors

Harald Langer

¹The Medizinische Klinik III, Universitätsklinikum Tübingen, Eberhard-Karls-Universität Tübingen, Tübingen, Germany
Andreas E. May

¹The Medizinische Klinik III, Universitätsklinikum Tübingen, Eberhard-Karls-Universität Tübingen, Tübingen, Germany
Andreas Bültmann

¹The Medizinische Klinik III, Universitätsklinikum Tübingen, Eberhard-Karls-Universität Tübingen, Tübingen, Germany
Meinrad Gawaz

¹The Medizinische Klinik III, Universitätsklinikum Tübingen, Eberhard-Karls-Universität Tübingen, Tübingen, Germany

Abstract

Summary

Cell adhesion and proteolytic matrix degradation are central processes in atherosclerosis. Being a member of the family of ADAMs (“a disintegrin and metalloproteinase”), metargidin (ADAM15) combines a metalloproteinase domain and an RGD aminoacid sequence. We studied the potential role of ADAM15 as an adhesion receptor on endothelial cells and interactions between platelets and ADAM15 with respect to platelet adhesion, activation and thrombus formation. ADAM15 was found to be expressed on cultured endothelial cells (HUVEC). Platelet adhesion to immobilized recombinantADAM15 was effectively enhanced under both static and high shear rate conditions reaching the maximum level of adhesion to fibrinogen. Consistently, platelet adhesion onto ADAM15 overexpressing endothelial cells was significantly increased. Adhesion to ADAM15 was reduced by blockade of GPIIb-IIIa using neutralizing anti-α_IIbβ₃ mAbs (7E3, 2G12), but not by anti-α_vβ₃ (LM609). Soluble ADAM15 binds to activated but not to resting GPIIb-IIIa. Moreover, platelets adherent to ADAM15 additionally attracted platelets under high shear rates indicating an initial role of platelet- ADAM15 interactions for thrombus formation. Furthermore, incubation of platelets with solubleADAM15 showed a dose-dependent increase in secretion of CD62P and CD40L. ADAM15 is expressed on endothelial cells and can serve as an adhesion receptor for platelets via GPIIb-IIIa binding. Platelet adhesion to ADAM15 leads to platelet activation, secretion and promotes thrombus formation. Thus, ADAM15 may represent a novel target for antithrombotic strategies in cardiovascular pathologies.

Keywords

ADAM15 - platelets - endothelium - integrin - atherosclerosis

Volltext

Referenzen

References
1 Ross R. Atherosclerosis–an inflammatory disease.. N Engl J Med 1999; 340: 115-26.
2 Blobel CP, Wolfsberg TG, Turck CW. et al. A potential fusion peptide and an integrin ligand domain in a protein active in sperm-egg fusion.. Nature 1992; 356: 248-52.
3 Wolfsberg TG, Bazan JF, Blobel CP. et al. The precursor region of a protein active in sperm-egg fusion contains a metalloprotease and a disintegrin domain: structural, functional, and evolutionary implications.. Proc Natl Acad Sci U S A 1993; 90: 10783-7.
4 White JM. ADAMs: modulators of cell-cell and cell-matrix interactions.. Curr Opin Cell Biol 2003; 15: 598-606.
5 Herren B, Raines EW, Ross R. Expression of a disintegrin- like protein in cultured human vascular cells and in vivo.. FASEB J 1997; 11: 173-80.
6 Nath D, Slocombe PM, Stephens PE. et al. Interaction of metargidin (ADAM-15) with αvβ3 and α5β1 integrins on different haemopoietic cells.. J Cell Sci 1999; 112: 579-87.
7 Kratzschmar J, Lum L, Blobel CP. Metargidin, a membrane-anchored metalloprotease-disintegrin protein with an RGD integrin binding sequence.. J Biol Chem 1996; 271: 4593-6.
8 Gawaz MP, Loftus JC, Bajt ML. et al. Ligand bridging mediates integrin alpha IIb beta 3 (platelet GPIIBIIIA) dependent homotypic and heterotypic cell-cell interactions.. J Clin Invest 1991; 88: 1128-34.
9 Horiuchi K, Weskamp G, Lum L. et al. Potential role for ADAM15 in pathological neovascularization in mice.. Mol Cell Biol 2003; 23: 5614-24.
10 Bombeli T, Schwartz BR, Harlan JM. Adhesion of activated platelets to endothelial cells: evidence for a GPIIbIIIa-dependent bridging mechanism and novel roles for endothelial intercellular adhesion molecule 1 (ICAM-1), αvβ3 integrin, and GPIbα.. J Exp Med 1998; 187: 329-39.
11 Gawaz M, Neumann FJ, Dickfeld T. et al. Activated platelets induce monocyte chemotactic protein-1 secretion and surface expression of intercellular adhesion molecule-1 on endothelial cells.. Circulation 1998; 98: 1164-71.
12 Gawaz M, Brand K, Dickfeld T. et al. Platelets induce alterations of chemotactic and adhesive properties of endothelial cells mediated through an interleukin- 1-dependent mechanism. Implications for atherogenesis.. Atherosclerosis 2000; 148: 75-85.
13 May AE, Kalsch T, Massberg S. et al. Engagement of glycoprotein IIb/IIIa (αIIbβ3) on platelets upregulates CD40L and triggers CD40L-dependent matrix degradation by endothelial cells.. Circulation 2002; 106: 2111-7.
14 Bajt ML, Loftus JC, Gawaz MP. et al. Characterization of a gain of function mutation of integrin alpha IIb beta 3 (platelet glycoprotein IIb-IIIa).. J Biol Chem 1992; 267: 22211-6.
15 O'Toole TE, Loftus JC, Du XP. et al. Affinity modulation of the alpha IIb beta 3 integrin (platelet GPIIb- IIIa) is an intrinsic property of the receptor.. Cell Regul 1990; 1: 883-93.
16 Peter K, O'Toole TE. Modulation of cell adhesion by changes in alpha L beta 2 (LFA-1, CD11a/CD18) cytoplasmic domain/cytoskeleton interaction.. J Exp Med 1995; 181: 315-26.
17 Ungerer M, Peluso M, Gillitzer A. et al. Generation of functional culture-derived platelets from CD34+ progenitor cells to study transgenes in the platelet environment.. Circ Res 2004; 95: 36-44.
18 Savage B, Saldivar E, Ruggeri ZM. Initiation of platelet adhesion by arrest onto fibrinogen or translocation on von Willebrand factor.. Cell 1996; 84: 289-97.
19 Tangelder GJ, Slaaf DW, Arts T. Wall shear rate in arterioles in vivo: least estimates from platelet velocity profiles.. Am J Physiol 1988; 254: 1059-64.
20 Al Fakhri N, Wilhelm J, Hahn M. et al. Increased expression of disintegrin-metalloproteinases ADAM-15 and ADAM-9 following upregulation of integrins alpha5beta1 and alphavbeta3 in atherosclerosis.. J Cell Biochem 2003; 89: 808-23.
21 Herren B. ADAM-mediated shedding and adhesion: a vascular perspective.. News Physiol Sci 2002; 17: 73-6.
22 Zhang XP, Kamata T, Yokoyama K. et al. Specific interaction of the recombinant disintegrin-like domain of MDC-15 (metargidin, ADAM-15) with integrin alphavbeta3.. J Biol Chem 1998; 273: 7345-50.
23 Massberg S, Brand K, Gruner S. et al. A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation.. J Exp Med 2002; 196: 887-96.
24 Plow EF, Byzova T. The biology of glycoprotein IIb-IIIa.. Coron Artery Dis 1999; 10: 547-51.
25 Henn V, Slupsky JR, Grafe M. et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells.. Nature 1998; 391: 591-4.
26 Heeschen C, Dimmeler S, Hamm CW. et al. Soluble CD40 ligand in acute coronary syndromes.. N Engl J Med 2003; 348: 1104-11.