Expression and function of syndecan-4 in human platelets

Summary

Platelet recruitment crucially depends on amplification systems provided by autocrine and paracrine factors such as adenosine diphosphate. In inflammatory states, consumption of coagulation proteins, such as antithrombin aggravates the procoagulant state. In this study, we report that platelets express synde-can-4, an antithrombin-binding cell surface heparan sulphate proteoglycan, whose ligation with antithrombin inhibits activated platelet-dependent superoxide anion release from neut-rophils by the limitation of adenosine diphosphate and adeno-sine triphosphate secretion in activated platelets. Adenosine triphosphate-induced platelet aggregation is reduced after treatment of platelets with antithrombin, which is reversed by blockade of syndecan-4. We further observed that antithrombin limits CD40 ligand expression in adenosine diphosphate-activated platelets and inhibits the shedding of syndecan-4 from activated platelets. Syndecan-4 appears to be directly involved in regulating platelet aggregation as anti-syndecan-4 antibody augments platelet aggregation. We suggest that antithrombin might exert beneficial effects in disseminated intravascular coagulation by reducing platelet activation, observed as inhibited CD40 ligand expression, syndecan-4 shedding, and adenosine diphosphate- and adenosine triphosphate-release from activated platelets with subsequent inhibition of neutrophil respiratory burst. From these data it is concluded that syndecan-4 may play important roles in the regulation of inflammatory effects of platelets.

Keywords

Cell-cell interactions - disseminated intravascular coagulation (DIC) / sepsis - antithrombin - heparins / glycosaminoglycans - platelet pharmacology

• References

• 1 Neame PB, Kelton JG, Walker IR. et al. Thrombocytopenia in septicemia: the role of disseminated intravascular coagulation. Blood 1980; 56: 88-92.
• 2 Warkentin TE, Aird WC, Rand JH. et al. Platelet-endothelial interactions: Sepsis, HIT, and antiphospholipid syndrome.hematology (Am Soc Hematol Educ Program). 2003: 497-519.
• 3 Dahlback B. Blood coagulation. Lancet 2000; 355: 1627-32.
• 4 Gailani D, Ho D, Sun MF. et al. Model for a factor IX activation complex on blood platelets: dimeric conformation of factor XIa is essential. Blood 2001; 97: 3117-22.
• 5 Monkovic DD, Tracy PB. Functional characterization of human platelet-released factor V and its activation by factor Xa and thrombin. J Biol Chem 1990; 265: 17132-40.
• 6 Hechler B, Leon C, Vial C. et al. The P2Y1 receptor is necessary for adenosine 5'-diphosphate-induced platelet aggregation. Blood 1998; 92: 152-9.
• 7 Daniel JL, Dangelmaier C, Jin J. et al. Role of intracellular signaling events in ADP-induced platelet aggregation. Thromb Haemost 1999; 82: 1322-6.
• 8 Bengtsson T, Zalavary S, Stendahl O. et al. Release of oxygen metabolites from chemoattractant-stimulated neutrophils is inhibited by resting platelets: role of extracellular adenosine and actin polymerization. Blood 1996; 87: 4411-23.
• 9 Kaul S, Waack BJ, Padgett RC. et al. Interaction of human platelets and leukocytes in modulation of vascular tone. Am J Physiol 1994; 266: H1706-1714.
• 10 Kaneider NC, Egger P, Dunzendorfer S. et al. Rho- GTPase-dependent platelet-neutrophil interaction affected by HMG-CoA reductase inhibition with altered adenosine nucleotide release and function. Arterioscler Thromb Vasc Biol 2002; 22: 1029-35.
• 11 Warren BL, Eid A, Singer P. et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 2001; 286: 1869-7.
• 12 Hoffmann JN, Vollmar B, Laschke MW. et al. Adverse effect of heparin on antithrombin action during endotoxemia: microhemodynamic and cellular mechanisms. Thromb Haemost 2002; 88: 242-52.
• 13 Kaneider NC, Egger P, Dunzendorfer S. et al. Syndecan- 4 as antithrombin receptor of human neutrophils. Biochem Biophys Res Commun 2001; 287: 42-6.
• 14 Kaneider NC, Forster E, Mosheimer B. et al. Syndecan-4-dependent signaling in the inhibition of endotoxin-induced endothelial adherence of neutrophils by antithrombin. Thromb Haemost 2003; 90: 1150-7.
• 15 Kaneider NC, Reinisch CM, Dunzendorfer S. et al. Syndecan-4 mediates antithrombin-induced chemotaxis of human peripheral blood lymphocytes and monocytes. J Cell Sci 2002; 115: 227-36.
• 16 Fitzgerald ML, Wang Z, Park PW. et al. Shedding of syndecan-1 and –4 ectodomains is regulated by multiple signaling pathways and mediated by a TIMP- 3-sensitive metalloproteinase. J Cell Biol 2000; 148: 811-24.
• 17 Damus PS, Rosenberg RD. Antithrombin-heparin cofactor. Methods Enzymol 1976; 45: 653-69.
• 18 Wiedermann CJ, Niedermuhlbichler M, Braunsteiner H, Widermann CJ. Priming of polymorphonuclear neutrophils by atrial natriuretic peptide in vitro. J Clin Invest 1992; 89: 1580-6.
• 19 Kaneider NC, Egger P, Dunzendorfer S. et al. Reversal of thrombin-induced deactivation of CD39/ATPDase in endothelial cells by HMG-CoA reductase inhibition: effects on Rho-GTPase and adenosine nucleotide metabolism. Arterioscler Thromb Vasc Biol 2002; 22: 894-900.
• 20 Kindness G, Williamson FB, Long WF. Inhibition by antithrombin III of carrageenan- and xylan SP54-induced aggregation of human blood platelets [proceedings]. Biochem Soc Trans 1980; 8: 84-5.
• 21 Carrell RW. How serpins are shaping up. Science 1999; 285: 1
• 22 Di Virgilio F, Solini A. P2 receptors: new potential players in atherosclerosis. Br J Pharmacol 2002; 135: 831-42.
• 23 Schiffrin EL. The endothelium and control of blood vessel function in health and disease. Clin Invest Med 1994; 17: 602-20.
• 24 Chung AW, Jurasz P, Hollenberg MD. et al. Mechanisms of action of proteinase-activated receptor agonists on human platelets. Br J Pharmacol 2002; 135: 1123-32.
• 25 Bernfield M, Gotte M, Park PW. et al. Functions of cell surface heparan sulfate proteoglycans. Annu Rev Biochem 1999; 68: 729-77.
• 26 Lee JC, Laydon JT, McDonnell PC. et al. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 1994; 372: 739-46.
• 27 Dangelmaier C, Jin J, Daniel JL. et al. The P2Y1 receptor mediates ADP-induced p38 kinase-activating factor generation in human platelets. Eur J Biochem 2000; 267: 2283-9.
• 28 May AE, Kalsch T, Massberg S. et al. Engagement of glycoprotein IIb/IIIa (alpha(IIb)beta3) on platelets upregulates CD40L and triggers CD40L-dependent matrix degradation by endothelial cells. Circulation 2002; 106: 2111-7.
• 29 Inwald DP, McDowall A, Peters MJ. et al. CD40 is constitutively expressed on platelets and provides a novel mechanism for platelet activation. Circ Res 2003; 92: 1041-8.
• 30 Esmon CT. The regulation of natural anticoagulant pathways. Science 1987; 235: 1348-52.
• 31 Dunzendorfer S, Kaneider N, Rabensteiner A. et al. Cell-surface heparan sulfate proteoglycan-mediated regulation of human neutrophil migration by the serpin antithrombin III. Blood 2001; 97: 1079-85.
• 32 Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999; 341: 586-92.