Antiphospholipid antibodies induce vascular functional changes in mice: a mechanism of vascular lesions in antiphospholipid syndrome?

Abstract

A premature atherosclerosis has been presumed in patients with antiphospholipid syndrome. The potential role of antiphospholipid antibodies in the development of atheroma is rather controversial. In this study, we tested the hypothesis that antiphospholipid antibodies could induce atherosclerosis via vascular functional changes. CD1 mice received one single injection of antiphospholipid monoclonal antibodies derived from male (BXSB × NZW) F1 mice with a lupus-like disease associated with an antiphospholipid syndrome and coronary artery disease. One week later, first-order mesenteric arteries (diameter 220–260 μm) were isolated and mounted on a small-vessel myograph for the measurement of the relaxation responses to acetylcholine or the NO donor nitroprusside after precontraction by phenylephrine. Five out of eight antiphospholipid monoclonal antibodies reduced the response to acetylcholine compared with control mice, and this effect was especially marked with one of them. No change in the response to nitroprusside was observed. The impairment was maintained after 3 weeks of treatment and appeared related to a moderate decrease in NO-mediated responses and a marked decrease in prostanoid-mediated relaxations. These vascular functional changes could be prevented by chronic treatment with statins or aspirin. These data could constitute additional elements supporting a direct pathogenic role of antiphospholipid antibodies. We suggest that a sub-population of these autoantibodies could be responsible for the endothelial dysfunction observed in antiphospholipid syndrome.

Keywords

antiphospholipid vascular functional changes atherosclerosis

Get full access to this article

View all access options for this article.

References

1 Manzi S Meilahn EN Rairie JE . Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol 1997; 145: 408 – 415 .

2 Hughes GR Harris NN Gharavi AE . The anticardiolipin syndrome. J Rheumatol 1986; 13: 486 – 489 .

3 Wilson WA Gharavi AE Koike T . International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 1999; 42: 1309 – 1311 .

4 Galli M Comfurius P Maassen C . Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet 1990; 335: 1544 – 1547 .

5 McNeil HP Simpson RJ Chesterman CN Krilis SA . Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta 2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci U S A 1990; 87: 4120 – 4124 .

6 Vaarala O Alfthan G Jauhiainen M . Crossreaction between antibodies to oxidised low-density lipoprotein and to cardiolipin in systemic lupus erythematosus. Lancet 1993; 341: 923 – 925 .

7 Romero FI Amengual O Atsumi T . Arterial disease in lupus and secondary antiphospholipid syndrome: association with anti-beta2-glycoprotein I antibodies but not with antibodies against oxidized low-density lipoprotein. Br J Rheumatol 1998; 37: 883 – 888 .

8 Hashimoto Y Kawamura M Ichikawa K . Anticardiolipin antibodies in NZW x BXSB F1 mice. A model of antiphospholipid syndrome. J Immunol 1992; 149: 1063 – 1068 .

9 Hang LM Izui S Dixon FJ . (NZW x BXSB)F1 hybrid. A model of acute lupus and coronary vascular disease with myocardial infarction. J Exp Med 1981; 154: 216 – 221 .

10.

10 Yoshida H Fujiwara H Fujiwara T Ikehara S Hamashima Y . Quantitative analysis of myocardial infarction in (NZW x BXSB)F1 hybrid mice with systemic lupus erythematosus and small coronary artery disease. Am J Pathol 1987; 129: 477 – 485 .

11.

11 Yla-Herttuala S Palinski W Butler SW . Rabbit and human atherosclerotic lesions contain IgG that recognizes epitopes of oxidized LDL. Arterioscler Thromb 1994; 14: 32 – 40 .

12.

12 Nityanand S Bergmark C de Faire U . Antibodies against endothelial cells and cardiolipin in young patients with peripheral atherosclerotic disease. J Intern Med 1995; 238: 437 – 443 .

13.

13 Shaw PX Goodyear CS Chang MK Witztum JL Silverman GJ . The autoreactivity of anti-phosphorylcholine antibodies for atherosclerosis-associated neo-antigens and apoptotic cells. J Immunol 2003; 170: 6151 – 6157 .

14.

14 Matsuura E Koike T . Accelerated atheroma and anti-beta2-glycoprotein I antibodies. Lupus 2000; 9: 210 – 216 .

15.

15 Shoenfeld Y Harats D George J . Atherosclerosis and the antiphospholipid syndrome: a link unravelled? Lupus 1998; 7: S140 – S143 .

16.

16 Becarevic M Andrejevic S Bonaci-Nikolic B . Anti-oxLDL antibodies – marker for arterial thromboses in antiphospholipid syndrome? Clin Lab 2005; 51: 279 – 283 .

17.

17 Matsuura E Kobayashi K Hurley BL Lopez LR . Atherogenic oxidized low-density lipoprotein/beta2-glycoprotein I (oxLDL/beta2GPI) complexes in patients with systemic lupus erythematosus and antiphospholipid syndrome. Lupus 2006; 15: 478 – 483 .

18.

18 Mizutani H Engelman RW Kinjoh K . Prevention and induction of occlusive coronary vascular disease in autoimmune (W/B)F1 mice by haploidentical bone marrow transplantation: possible role for anticardiolipin autoantibodies. Blood 1993; 82: 3091 – 3097 .

19.

19 George J Harats D Gilburd B . Adoptive transfer of beta(2)-glycoprotein I-reactive lymphocytes enhances early atherosclerosis in LDL receptor-deficient mice. Circulation 2000; 102: 1822 – 1827 .

20.

20 Nicolo D Goldman BI Monestier M . Reduction of atherosclerosis in low-density lipoprotein receptor-deficient mice by passive administration of antiphospholipid antibody. Arthritis Rheum 2003; 48: 2974 – 2978 .

21.

21 Ameli S Hultgardh-Nilsson A Regnstrom J . Effect of immunization with homologous LDL and oxidized LDL on early atherosclerosis in hypercholesterolemic rabbits. Arterioscler Thromb Vasc Biol 1996; 16: 1074 – 1079 .

22.

22 Palinski W Miller E Witztum JL . Immunization of low density lipoprotein (LDL) receptor-deficient rabbits with homologous malondialdehyde-modified LDL reduces atherogenesis. Proc Natl Acad Sci U S A 1995; 92: 821 – 825 .

23.

23 Sherer Y Shoenfeld Y . Antiphospholipid antibodies: are they pro-atherogenic or an epiphenomenon of atherosclerosis? Immunobiology 2003; 207: 13 – 16 .

24.

24 Nicolo D Monestier M . Antiphospholipid antibodies and atherosclerosis. Clin Immunol 2004; 112: 183 – 189 .

25.

25 Meroni PL Parati G Tincani A Mari D Tedesco F . Inflammatory response and the endothelium. Thromb Res 2004; 114: 329 – 334 .

26.

26 Pierangeli SS Espinola RG Liu X Harris EN . Thrombogenic effects of antiphospholipid antibodies are mediated by intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, and P-selectin. Circ Res 2001; 88: 245 – 250 .

27.

27 Kaplanski G Cacoub P Farnarier C . Increased soluble vascular cell adhesion molecule 1 concentrations in patients with primary or systemic lupus erythematosus-related antiphospholipid syndrome: correlations with the severity of thrombosis. Arthritis Rheum 2000; 43: 55 – 64 .

28.

28 Frijns CJ Derksen RH De Groot PG Algra A Fijnheer R . Lupus anticoagulant and history of thrombosis are not associated with persistent endothelial cell activation in systemic lupus erythematosus. Clin Exp Immunol 2001; 125: 149 – 154 .

29.

29 Bonetti PO Lerman LO Lerman A . Endothelial dysfunction. A marker of atherosclerotic risk. Arterioscler Throm Vasc Biol 2003; 23: 168 – 175 .

30.

30 Wilkinson IB Qasem A McEniery CM . Nitric oxide regulates local arterial distensibility in vivo. Circulation 2002; 105: 213 – 217 .

31.

31 Kinlay S Creager MA Fukumoto M . Endothelium-derived nitric oxide regulates arterial elasticity in human arteries in vivo. Hypertension 2001; 38: 1049 – 1053 .

32.

32 Mulvany MJ Halpern W . Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. Circ Res 1977; 41: 19 – 26 .

33.

33 Richard V Kaeffer N Tron C Thuillez C . Ischemic preconditioning protects against coronary endothelial dysfunction induced by ischemia and reperfusion. Circulation 1994; 89: 1254 – 1261 .

34.

34 Favre J Musette P Douin-Echinard V . Toll-like receptors 2-deficient mice are protected against postischemic coronary endothelial dysfunction. Arterioscler Thromb Vasc Biol 2007; 27: 1064 – 1067 .

35.

35 Gilbert D Lopez B Parain J Koutouzov S Tron F . Overlap of the anti-cardiolipin and anti-nucleosome responses of the (NZW XBXSB)F1 mouse strain: a new pattern of cross-reactivity for lupus-related autoantibodies. Eur J Immunol 2000; 30: 3271 – 3280 .

36.

36 Thebault S Gilbert D Machour N . Two-dimensional electrophoresis and mass spectrometry identification of proteins bound by a murine monoclonal anti-cardiolipin antibody: a powerful technique to characterize the cross-reactivity of a single autoantibody. Electrophoresis 2000; 21: 2531 – 2539 .

37.

37 Lartigue A Drouot L Jouen F . Association between anti-nucleophosmin and anti-cardiolipin antibodies in (NZW x BXSB)F1 mice and human systemic lupus erythematosus. Arthritis Res Ther 2005; 7: R1394 – 1403 .

38.

38 Li XZ McNeilage LJ Whittingham S . Autoantibodies to the major nucleolar phosphoprotein B23 define a novel subset of patients with anticardiolipin antibodies. Arthritis Rheum 1989; 32: 1165 – 1169 .

39.

39 Bonetti PO Lerman LO Lerman A . Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol 2003; 23: 168 – 175 .

40.

40 Carreras LO Vermylen JG . “Lupus” anticoagulant and thrombosis – possible role of inhibition of prostacyclin formation. Thromb Haemost 1982; 48: 38 – 40 .

41.

41 Cai H Harrison DG . Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 2000; 87: 840 – 844 .

42.

42 Cines DB Pollak ES Buck CA . Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 1998; 91: 3527 – 3561 .

43.

43 Laufs U La Fata V Plutzky J Liao JK . Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998; 97: 1129 – 1135 .

44.

44 Essig M Nguyen G Prie D . 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase fibrinolytic activity in rat aortic endothelial cells. Role of geranylgeranylation and Rho proteins. Circ Res 1998; 83; 683 – 690 .

45.

45 Meroni PL Raschi E Camera M . Endothelial activation by aPL: a potential pathogenetic mechanism for the clinical manifestations of the syndrome. J Autoimmunity 2000; 15: 237 – 240 .

46.

46 Aprahamian T Bonegio R Rizzo J . Simvastatin treatment ameliorates autoimmune disease associated with accelerated atherosclerosis in a murine lupus model. J Immunol 2006; 177: 3028 – 3034 .

47.

47 Lawman S Mauri C Jury EC Cook HT Ehrenstein MR . Atorvastatin inhibits autoreactive B cell activation and delays lupus development in New Zealand black/white F1 mice. J Immunol 2004; 173: 7641 – 7646 .

48.

48 Ferrara DE Liu X Espinola RG . Inhibition of the thrombogenic and inflammatory properties of antiphospholipid antibodies by fluvastatin in an in vivo animal model. Arthritis Rheum 2003; 48: 3272 – 3279 .

49.

49 Abud-Mendoza C de la Fuente H Cuevas-Orta E . Therapy with statins in patients with refractory rheumatic diseases: a preliminary study. Lupus 2003; 12: 607 – 11 .

50.

50 Dunoyer-Geindre S Kruithof EK Boehlen F . Aspirin inhibits endothelial cell activation induced by antiphospholipid antibodies. J Thromb Haemost 2004; 2: 1176 – 1181 .

51.

51 Grosser N Schroder H . Aspirin protects endothelial cells from oxidant damage via the nitric oxide-cGMP pathway. Arterioscler Thromb Vasc Biol 2003; 23: 1345 – 1351 .

52.

52 Kopp E Ghosh S . Inhibition of NF-kappa B by sodium salicylate and aspirin. Science 1994; 265: 956 – 959 .

53.

53 Pierce JW Read MA Ding H Luscinskas FW Collins T . Salicylates inhibit I kappa B-alpha phosphorylation, endothelial-leukocyte adhesion molecule expression, and neutrophil transmigration. J Immunol 1996; 156: 3961 – 3969 .

54.

54 Muller DN Heissmeyer V Dechend R . Aspirin inhibits NF-kappaB and protects from angiotensin II-induced organ damage. FASEB J 2001; 15: 1822 – 1824 .

55.

55 Leung MH Heaton S Skan J . Mortality and malignancy in the multi-ethnic Birmingham Lupus Cohort: aspirin use is beneficial and non-Caucasian origin is not associated with a poor outcome. Rheumatology 2002; 41: S17 .