Fluvastatin increases the expression of adhesion molecules, monocyte chemoattractant protein-1 and tissue factor in HUVEC stimulated by patient IgG fractions containing antiphospholipid antibodies

Summary

The presence of antiphospholipid antibodies (APLA) is associated with an increased risk of recurrent thrombosis and pregnancy loss. APLA are able to activate endothelial cells (EC) and induce an increase in the expression of inflammatory marker proteins, such as leukocyte adhesion molecules, tissue factor or the monocyte chemoattractant protein-1 (MCP-1). Our objective was to investigate the effect of statins on EC activation induced by APLA in vitro. IgG was purified from the plasma of six patients with APLA and from healthy controls. EC were incubated with patient IgG or with control IgG, in the presence or absence of 5μM of fluvastatin, and expression of the leukocyte adhesion molecules, VCAM-1 and E-selectin, analyzed by flow cytometry and by quantitative reverse transcriptase-PCR (QRT-PCR).The expression of tissue factor and the chemokine MCP-1 was analyzed by QRT-PCR alone. Incubation of EC with patient IgG increased the expression of VCAM-1, E-selectin, tissue factor and MCP-1. Prior treatment of the cells with fluvastatin further increased the expression of these proteins. The fluvastatin effect was reversed by co-incubation with mevalonate or geranylgeranylpyrophosphate and mimicked by the geranylgeranyl transferase inhibitor GGTI-286. Our results show that in cultured human EC, statins increase the extent of inflammatory activation induced by APLA. This effect appears to be mediated by an inhibitory effect of statins on one or more geranylgeranylated protein(s).

Keywords

Antiphospholipid antibodies - endothelial cells - statins - tissue factor - cell adhesion molecules

• References

• 1 Carlos TM, Harlan JM. Leukocyte-endothelial adhesion molecules.. Blood 1994; 84: 2068-101.
• 2 Ikeda U, Takahashi M, Shimada K. Monocyte endothelial cell interaction in atherogenesis and thrombosis.. Clin Cardiol 1998; 21: 11-4.
• 3 Lo SK, Cheung A, Zheng Q. et al. Induction of tissue factor on monocytes by adhesion to endothelial cells.. J Immunol 1995; 154: 4768-77.
• 4 Kornberg A, Renaudineau Y, Blank M. et al Anti- β 2-Glycoprotein I antibodies and anti-endothelial cell antibodies induce tissue factor in endothelial cells.. IMAJ 2000; 2: 27-31.
• 5 Meroni PL, Raschi E, Testoni C. et al Statins prevent endothelial cell activation induced by antiphospholipid (Anti-β 2-Glycoprotein I) antibodies.. Arthritis Rheum 2001; 44: 2870-8.
• 6 Dunoyer-Geindre S, de Moerloose P, Galve-de Rochemonteix B. et al NFkappaB is an essential intermediate in the activation of endothelial cells by antibeta( 2)-glycoprotein 1 antibodies.. Thromb Haemost 2002; 88: 851-7.
• 7 Pierangeli SS, Colden-Stanfield M, Liu X. et al Antiphospholipid antibodies from antiphospholipid syndrome patients activate endothelial cells in vitro and in vivo.. Circulation 1999; 99: 1997-2002.
• 8 Pierangeli SS, Gharavi AE, Harris EN. Experimental thrombosis and antiphospholipid antibodies: new insight.. J Autoimmun 2000; 15: 241-7.
• 9 Kaplanski G, Cacoub P, Farnarier C. et al Increased soluble vascular cell adhesion molecule 1 concentrations in patients with primary or systemic lupus erythematosus-related antiphospholipid syndrome: correlation with the severity of thrombosis.. Arthritis Rheum 2000; 43: 55-64.
• 10 Combes V, Simon AC, Grau GE. et al In vitro generation of endothelial microparticles and possible prothrombotic activity in patients with lupus anticoagulant.. J Clin Invest 1999; 104: 93-102.
• 11 Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy- 3-methylglutaryl coenzyme A reductase in- hibitors.. Arterioscler Thromb Vasc Biol 2001; 2: 1712-9.
• 12 Wagner AH, Gebauer M, Güldenzoph B. et al 3-hydroxy- 3-methylglutaryl coenzyme A reductase-independent inhibition of CD40 expression by atorvastatin in human endothelial cells.. Arterioscler Thromb Vasc Biol 2002; 22: 1784-9.
• 13 Sadeghi MM, Collinge M, Pardi R. et al Simvastatin modulates cytokine-mediated endothelial cell adhesion molecule induction: involvement of an inhibitory G protein.. J Immunol 2000; 165: 2712-8.
• 14 Schmidt A, Goepfert C, Feitsma K. et al Lovastatin- stimulated superinduction of E-selectin, ICAM-1 and VCAM-1 in TNFα activated human vascular endothelial cells.. Atherosclerosis 2002; 164: 57-64.
• 15 Dimitrova Y, Dunoyer-Geindre S, Reber G. et al Effect of statins on adhesion molecule expression in endothelial cells.. J Thromb Haemost 2003; 1: 2290-9.
• 16 Bernot D, Benoliel AM, Peiretti F. et al Effect of atorvastatin on adhesive phenotype of human endothelial cells activated by tumor necrosis factor alpha.. J Cardiovasc Pharmacol 2003; 41: 316-24.
• 17 Ferrara DE, Liu X, Espinola RG. et al Inhibition of the thrombogenic and inflammatory properties of antiphospholipid antibodies by fluvastatin in an in vivo animal model.. Arthritis Rheum 2003; 48: 3272-9.
• 18 Dunoyer-Geindre S, Kruithof EKO, Boehlen F. et al Aspirin inhibits endothelial cell activation induced by antiphopsholipid antibodies.. J Thromb Haemost 2004; 2: 1176-81.
• 19 Reber G, Arvieux J, Comby E. et al Multicenter evaluation of nine commercial kits for the quantitation of anticardiolipin antibodies.. Thromb Haemost 1995; 73: 444-52.
• 20 Reber G, Schousboe I, Tincani A. et al Inter-laboratory variability of anti-beta2-glycoprotein I measurement. A collaborative study in the frame of the European Forum on Antiphospholipid Antibodies Standardization Group.. Thromb Haemost 2002; 88: 66-73.
• 21 Jaffe EA, Nachman RL, Becker CG. et al Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria.. J Clin Invest 1973; 52: 2745-56.
• 22 Dunoyer-Geindre S, Kruithof EK, Galve-de Rochemonteix B. et al Localization of beta2-glycoprotein 1 in late endosomes of human endothelial cells.. Thromb Haemost 2001; 85: 903-7.
• 23 Cho CS, Cho ML, Chen PP. et al Antiphospholipid antibodies induce monocyte chemoattractant protein-1 in endothelial cells.. J Immunol 2002; 168: 4209-15.
• 24 Koh KK. Effects of statins on vascular wall: vasomotor function, inflammation, and plaque stability.. Cardiovasc Res 2000; 47: 648-57.
• 25 Werner N, Nickenig G, Laufs U. Pleiotropic effects of HMG-CoA reductase inhibitors.. Basic Res Cardiol 2002; 97: 105-16.
• 26 Case CC, Ballantyne CM. Statins and inflammatory markers.. Curr Atheroscler Rep 2002; 4: 42-7.
• 27 Colli S, Eligini S, Lalli M. et al Vastatins inhibit tissue factor in cultured human macrophages. A novel mechanism of protection against atherothrombosis.. Arterioscler Thromb Vasc Biol 1997; 17: 265-72.
• 28 Baetta R, Camera M, Comparato C. et al Fluvastatin reduces tissue factor expression and macrophage accumulation in carotid lesions of cholesterol-fed rabbits in the absence of lipid lowering.. Arterioscler Thromb Vasc Biol 2002; 22: 692-8.
• 29 Meroni PL, Tremoli E. Modulation of adhesion molecule expression on endothelial cells: to be or not to be?. J Thromb Haemost 2003; 1: 2280-2.
• 30 Van Wetering S, van den Berk N, van Buul JD. et al VCAM-1-mediated Rac signaling controls endothelial cell-cell contacts and leukocyte transmigration.. Am J Physiol Cell Physiol 2003; 285: C343-52.
• 31 Kiener PA, Davis PM, Murray JL. et al Stimulation of inflammatory responses in vitro and in vivo by lipophilic HMG-CoA reductase inhibitors.. Int Immunopharmacol 2001; 1: 105-18.