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Human monoclonal IgG anticardiolipin antibodies induce nitric oxide synthase expression

      Abstract

      Objective

      Antiphospholipid antibodies are associated with increased risk of thrombosis, particularly as in antiphospholipid syndrome. This study aims to determine the acute effects of anticardiolipin antibodies on nitric oxide production and vascular function.

      Methods

      Ex vivo aortic rings from male Sprague Dawley rats were incubated with IgG monoclonal anticardiolipin antibody (IS4) or a non-specific IgG control. In organ baths, response to phenylephrine and acetlycholine was determined alone and with nitro-l-arginine methyl ester (l-NAME), 1400 W, d-arginine, l-arginine, sodium nitroprusside and cardiolipin. In vivo antibodies were injected into anaesthetised, spontaneously breathing male Sprague Dawley rats. Haemodynamic variables and serum nitric oxide were measured. Immunohistochemistry for iNOS and eNOS was performed in kidney vessels.

      Results

      Phenylepherine contraction was decreased in the IS4 group compared to controls (p < 0.001). l-NAME, 1400 W and cardiolipin, abolished this effect. l-Arginine caused significant relaxation in the IS4 group (p = 0.005). Mean arterial pressure in rats injected with IS4 was reduced compared to IgG and saline controls (p < 0.001). NO in plasma increased significantly after IS4 administration (p < 0.001). Immunohistochemistry showed increased iNOS expression in kidney arteries in the IS4 group, with no change in eNOS.

      Conclusion

      Anticardiolipin antibodies induce NO production acutely via increased expression of iNOS in both ex vivo and in vivo models.

      Keywords

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      References

        • Roubey R.A.
        Autoantibodies to phospholipid-binding plasma proteins: a new view of lupus anticoagulants and other “antiphospholipid” autoantibodies.
        Blood. 1994; 84: 2854-2867
        • Arnout J.
        • Vermylen J.
        Mechanism of action of beta2-glycoprotein I-dependent lupus anticoagulants.
        Lupus. 1998; 7: S23-S28
        • Roubey R.A.
        Mechanisms of autoantibody-mediated thrombosis.
        Lupus. 1998; 7: S114-S119
        • Khamashta M.A.
        • Hughes G.R.V.
        The antiphospholipid antibody syndrome.
        in: Maddison P.J. Isenberg D.A. Woo P. Glass D.N. Oxford textbook of rheumatology. Oxford Medical Publications, Oxford1998: 1202-1216
        • Joseph J.E.
        • Harrison P.
        • Mackie I.J.
        • et al.
        Platelet activation markers and the primary antiphospholipid syndrome (PAPS).
        Lupus. 1998; 7: S48-S51
        • Dobado-Berrios P.M.
        • Lopez-Pedrera C.
        • Velasco F.
        • et al.
        Increased levels of tissue factor mRNA in mononuclear blood cells of patients with primary antiphospholipid syndrome.
        Thromb Haemost. 1999; 82: 1578-1582
        • Levy R.A.
        • Avvad E.
        • Oliveira J.
        • et al.
        Placental pathology in antiphospholipid syndrome.
        Lupus. 1998; 7: S81-S85
        • Meroni P.L.
        • Raschi E.
        • Camera M.
        • et al.
        Endothelial activation by aPL: a potential pathogenetic mechanism for the clinical manifestations of the syndrome.
        J Autoimmun. 2000; 15: 237-240
        • Ames P.R.
        • Tommasino C.
        • Alves J.
        • et al.
        Antioxidant susceptibility of pathogenic pathways in subjects with antiphospholipid antibodies: a pilot study.
        Lupus. 2000; 9: 688-695
        • Iuliano L.
        • Pratico D.
        • Ferro D.
        • et al.
        Enhanced lipid peroxidation in patients positive for antiphospholipid antibodies.
        Blood. 1997; 90: 3931-3935
        • Ames P.R.
        • Nourooz-Zadeh J.
        • Tommasino C.
        • et al.
        Oxidative stress in primary antiphospholipid syndrome.
        Thromb Haemost. 1998; 79: 447-449
        • Delgado A.J.
        • Ames P.R.
        • Donohue S.
        • et al.
        Antibodies to high-density lipoprotein and beta2-glycoprotein I are inversely correlated with paraoxonase activity in systemic lupus erythematosus and primary antiphospholipid syndrome.
        Arthritis Rheum. 2002; 46: 2686-2694
        • Zhu M.
        • Olee T.
        • Le D.T.
        • et al.
        Characterization of IgG monoclonal anti-cardiolipin/anti-beta2GP1 antibodies from two patients with antiphospholipid syndrome reveals three species of antibodies.
        Br J Haematol. 1999; 105: 102-109
        • Giovannoni G.
        • Land J.M.
        • Keir G.
        • et al.
        Adaptation of the nitrate reductase and Griess reaction methods for the measurement of serum nitrate plus nitrite levels.
        Ann Clin Biochem. 1997; 34: 193-198
        • Freedman J.E.
        • Loscalzo J.
        • Barnard M.R.
        • et al.
        Nitric oxide released from activated platelets inhibits platelet recruitment.
        J Clin Invest. 1997; 100: 350-356
        • Bouchie J.L.
        • Hansen H.
        • Feener E.P.
        Natriuretic factors and nitric oxide suppress plasminogen activator inhibitor-1 expression in vascular smooth muscle cells. Role of cGMP in the regulation of the plasminogen system.
        Arterioscler Thromb Vasc Biol. 1998; 18: 1771-1779
        • Lu J.L.
        • Schmiege III, L.M.
        • Kuo L.
        • et al.
        Downregulation of endothelial constitutive nitric oxide synthase expression by lipopolysaccharide.
        Biochem Biophys Res Commun. 1996; 225: 1-5
        • Parker J.L.
        • Adams H.R.
        Selective inhibition of endothelium-dependent vasodilator capacity by Escherichia coli endotoxemia.
        Circ Res. 1993; 72: 539-551
        • Delgado Alves J.
        • Davies N.A.
        • Mason L.
        • et al.
        Anticardiolipin antibody is associated with decreased paraoxonase activity and serum nitric oxide in a mouse model.
        Arthritis Rheum. 2002; 46: S230
        • Porta C.
        • Buggia I.
        • Bonomi I.
        • et al.
        Nitrite and nitrate plasma levels, as markers of nitric oxide synthesis, in antiphospholipid antibodies-related conditions and in thrombotic thrombocytopenic purpura.
        Thromb Haemost. 1997; 78: 965-967
        • Del Papa N.
        • Guidali L.
        • Spatola L.
        • et al.
        Relationship between anti-phospholipid and anti-endothelial cell antibodies III: beta 2 glycoprotein I mediates the antibody binding to endothelial membranes and induces the expression of adhesion molecules.
        Clin Exp Rheum. 1995; 13: 179-185
        • Meroni P.L.
        • Raschi E.
        • Testoni C.
        • et al.
        Statins prevent endothelial cell activation induced by antiphospholipid (anti-beta2-glycoprotein I) antibodies: effect on the proadhesive and proinflammatory phenotype.
        Arthritis Rheum. 2001; 44: 2870-2878
        • Cooke C.L.
        • Davidge S.T.
        Peroxynitrite increases iNOS through NF-kappaB and decreases prostacyclin synthase in endothelial cells.
        Am J Physiol Cell Physiol. 2002; 282: C395-C402