All Title Author
Keywords Abstract


Circulating Anti-Beta2-Glycoprotein I Antibodies Are Associated with Endothelial Dysfunction, Inflammation, and High Nitrite Plasma Levels in Patients with Intermittent Claudication

DOI: 10.1155/2013/268079

Full-Text   Cite this paper   Add to My Lib

Abstract:

Our aim is to investigate a possible association of circulating anti-beta2-glycoprotein I antibodies (ABGPI) with the endothelial dysfunction, nitric oxide bioactivity dysregulation, and the inflammatory status that surrounds peripheral arterial disease. We carried out an observational translational study, including 50 male patients with intermittent claudication and a healthy control group of 10 male subjects, age and sex matched with the cases. Flow-mediated arterial dilatation (FMAD) was assessed as a surrogate of endothelial dysfunction, and C-reactive protein (hsCRP) was determined as a marker of inflammation. Nitrite plasma levels were measured by colorimetric analysis. Circulating ABGPI titer was detected with indirect immunofluorescence. Titers <1?:?10 represented the reference range and the lower detection limit of the test. Circulating ABGPI titer ≥1?:?10 was detected in 21 (42%) patients and in none of the control subjects ( ). Patients with ABGPI titer ≥1?:?10 had a lower FMAD ( ). The CRP levels were higher in patients with ABGPI titer ≥1?:?10 ( ). The nitrite plasma levels were higher in patients with ABGPI titer ≥1?:?10 ( ). These data suggest that these circulating ABGPI may collaborate in the development of atherosclerosis; however, further prospective studies are required to establish a causal relationship. 1. Introduction The endothelium is responsible for maintaining the balance between the different factors involved in the vascular wall function. In atherosclerosis, this balance is broken, and the endothelium is no longer able to regulate vascular homeostasis. This situation causes endothelial dysfunction characterised by vasospasm, vasoconstriction, local coagulation alterations, abnormal fibrinolysis, and an increase in arterial wall cell proliferation. Endothelial dysfunction acts as a primary pathogenic event, as it occurs before structural change are evident on angiogram or ultrasound scan, and it is not correlated with the disease’s severity [1]. The loss of endothelial regulation has been attributed to a reduction in nitric oxide bioactivity and to an increased oxygen-free radical formation in the context of the proinflammatory status found in atherosclerosis [2, 3]. On the other hand, there is currently a wide variety of data pointing to a possible autoimmune origin of atherosclerosis [4–11]. This hypothesis is biologically plausible, as chronic vascular inflammation observed in atherosclerosis is based on the dysregulation of the immune system activity. In this context, circulating anti-beta2-glycoprotein I antibodies

References

[1]  F. J. Maldonado, J. D. H. Miralles, E. M. Aguilar, A. F. Gonzalez, J. R. M. García, and F. A. García, “Relationship between noninvasively measured endothelial function and peripheral arterial disease,” Angiology, vol. 60, no. 6, pp. 725–731, 2009.
[2]  L. J. Ignarro, G. Cirino, A. Casini, and C. Napoli, “Nitric oxide as a signaling molecule in the vascular system: an overview,” Journal of Cardiovascular Pharmacology, vol. 34, no. 6, pp. 879–886, 1999.
[3]  J. de Haro Miralles, E. Martínez-Aguilar, A. Florez, C. Varela, S. Bleda, and F. Acin, “Nitric oxide: link between endothelial dysfunction and inflammation in patients with peripheral arterial disease of the lower limbs,” Interactive Cardiovascular and Thoracic Surgery, vol. 9, no. 1, pp. 107–112, 2009.
[4]  P. Marrack, J. Kappler, and B. L. Kotzin, “Autoimmune disease: why and where it occurs,” Nature Medicine, vol. 7, no. 8, pp. 899–905, 2001.
[5]  G. K. Hansson and P. Libby, “The immune response in atherosclerosis: a double-edged sword,” Nature Reviews Immunology, vol. 6, no. 7, pp. 508–519, 2006.
[6]  X. Zhou, A. Nicoletti, R. Elhage, and G. K. Hansson, “Transfer of CD4+ T cells aggravates atherosclerosis in immunodeficient apolipoprotein E knockout mice,” Circulation, vol. 102, no. 24, pp. 2919–2922, 2000.
[7]  Q. Xu, R. Kleindienst, W. Waitz, H. Dietrich, and G. Wick, “Increased expression of heat shock protein 65 coincides with a population of infiltrating T lymphocytes in atherosclerotic lesions of rabbits specifically responding to heat shock protein 65,” Journal of Clinical Investigation, vol. 91, no. 6, pp. 2693–2702, 1993.
[8]  H. Perschinka, B. Wellenzohn, W. Parson et al., “Identification of atherosclerosis-associated conformational heat shock protein 60 epitopes by phage display and structural alignment,” Atherosclerosis, vol. 194, no. 1, pp. 79–87, 2007.
[9]  Y. Shoenfeld, R. Gerli, A. Doria et al., “Accelerated atherosclerosis in autoimmune rheumatic diseases,” Circulation, vol. 112, no. 21, pp. 3337–3347, 2005.
[10]  A. Broder, J. J. Chan, and C. Putterman, “Dendritic cells: an important link between antiphospholipid antibodies, endothelial dysfunction, and atherosclerosis in autoimmune and non-autoimmune diseases,” Clinical Immunology, vol. 146, no. 3, pp. 197–206, 2013.
[11]  G. Murdaca, B. M. Colombo, P. Cagnati, R. Gulli, F. Spano, and F. Puppo, “Endothelial dysfunction in rheumatic autoimmune diseases,” Atherosclerosis, vol. 224, no. 2, pp. 309–317, 2012.
[12]  E. Aslim, T. Hakki Akay, B. Bastürk et al., “The role of antiendothelial cell antibodies in the development and follow-up of coronary and peripheral arterial diseases,” Angiology, vol. 59, no. 2, pp. 209–213, 2008.
[13]  M. Franck, H. L. Staub, J. B. Petracco et al., “Autoantibodies to the atheroma component beta2-glycoprotein I and risk of symptomatic peripheral artery disease,” Angiology, vol. 58, no. 3, pp. 295–302, 2007.
[14]  C. Varela, J. de Haro, S. Bleda, L. Esparza, I. L. de Maturana, and F. Acin, “Anti-endothelial cell antibodies are associated with peripheral arterial disease and markers of endothelial dysfunction and inflammation,” Interactive Cardiovascular and Thoracic Surgery, vol. 13, no. 5, pp. 463–467, 2011.
[15]  I. Schousboe, “β 2-glycoprotein I: a plasma inhibitor of the contact activation of the intrinsic blood coagulation pathway,” Blood, vol. 66, no. 5, pp. 1086–1091, 1985.
[16]  J. Nimpf, H. Wurm, and G. M. Kostner, “β2-Glycoprotein-I (apo-H) inhibits the release reaction of human platelets during ADP-induced aggregation,” Atherosclerosis, vol. 63, no. 2-3, pp. 109–114, 1987.
[17]  A. Tincani, L. Spatola, E. Prati et al., “The anti-beta2-glycoprotein I activity in human anti-phospholipid syndrome sera is due to monoreactive low-affinity autoantibodies directed to epitopes located on native beta2-glycoprotein I and preserved during species' evolution,” Journal of Immunology, vol. 157, no. 12, pp. 5732–5738, 1996.
[18]  P. L. Meroni, E. Raschi, C. Testoni, and M. O. Borghi, “Endothelial cell activation by antiphospholipid antibodies,” Clinical Immunology, vol. 112, no. 2, pp. 169–174, 2004.
[19]  J. de Haro, F. Acin, A. Lopez-Quintana et al., “Direct association between C-reactive protein serum levels and endothelial dysfunction in patients with claudication,” European Journal of Vascular and Endovascular Surgery, vol. 35, no. 4, pp. 480–486, 2008.
[20]  T. Y. Carroll, M. J. Mulla, C. S. Han et al., “Modulation of trophoblast angiogenic factor secretion by antiphospholipid antibodies is not reversed by heparin,” The American Journal of Reproductive Immunology, vol. 66, no. 4, pp. 286–296, 2011.
[21]  M. Stalc, M. Tomsic, M. K. Jezovnik, and P. Poredos, “Endothelium-dependent and independent dilation capability of peripheral arteries in patients with systemic lupus erythematosus and antiphospholipid syndrome,” Clinical and Experimental Rheumatology, vol. 29, no. 4, pp. 616–623, 2011.
[22]  C. Mineo, “Inhibition of nitric oxide and antiphospholipid antibody-mediated thrombosis,” Current Rheumatology Reports, vol. 15, no. 5, article 324, 2013.
[23]  P. Kleinbongard, T. Rassaf, A. Dejam, S. Kerber, and M. Kelm, “Griess method for nitrite measurement of aqueous and protein-containing samples,” Methods in Enzymology, vol. 359, pp. 158–168, 2002.
[24]  N. Del Papa, L. Guidali, L. Spatola et al., “Relationship between anti-phospholipid and anti-endothelial cell antibodies III: β2 glycoprotein I mediates the antibody binding to endothelial membranes and induces the expression of adhesion molecules,” Clinical and Experimental Rheumatology, vol. 13, no. 2, pp. 179–185, 1995.
[25]  P. Kleinbongard, A. Dejam, T. Lauer et al., “Plasma nitrite reflects constitutive nitric oxide synthase activity in mammals,” Free Radical Biology and Medicine, vol. 35, no. 7, pp. 790–796, 2003.
[26]  S. Ramesh, C. N. Morrell, C. Tarango et al., “Antiphospholipid antibodies promote leukocyte-endothelial cell adhesion and thrombosis in mice by antagonizing eNOS via β2GPI and apoER2,” Journal of Clinical Investigation, vol. 121, no. 1, pp. 120–131, 2011.
[27]  J. E. Barbato and E. Tzeng, “Nitric oxide and arterial disease,” Journal of Vascular Surgery, vol. 40, no. 1, pp. 187–193, 2004.
[28]  B. R. Clapp, G. M. Hirschfield, C. Storry et al., “Inflammation and endothelial function: direct vascular effects of human C-reactive protein on nitric oxide bioavailability,” Circulation, vol. 111, no. 12, pp. 1530–1536, 2005.
[29]  T. J. Anderson, “Nitric oxide, atherosclerosis and the clinical relevance of endothelial dysfunction,” Heart Failure Reviews, vol. 8, no. 1, pp. 71–86, 2003.
[30]  T. Miyoshi, Y. Li, D. M. Shih et al., “Deficiency of inducible NO synthase reduces advanced but not early atherosclerosis in apolipoprotein E-deficient mice,” Life Sciences, vol. 79, no. 6, pp. 525–531, 2006.
[31]  M. B. Pepys and G. M. Hirschfield, “C-reactive protein: a critical update,” Journal of Clinical Investigation, vol. 111, no. 12, pp. 1805–1812, 2003.
[32]  B. Buttari, E. Profumo, A. Capozzi, M. Sorice, and R. Riganò, “Oxidized human beta2-glycoprotein i: its impact on innate immune cells,” Current Molecular Medicine, vol. 11, no. 9, pp. 719–725, 2011.
[33]  E. Raschi, C. Testoni, D. Bosisio et al., “Role of the MyD88 transduction signaling pathway in endothelial activation by antiphospholipid antibodies,” Blood, vol. 101, no. 9, pp. 3495–3500, 2003.
[34]  J.-E. Alard, F. Gaillard, C. Daridon, Y. Shoenfeld, C. Jamin, and P. Youinou, “TLR2 is one of the endothelial receptors for β2-glycoprotein I,” Journal of Immunology, vol. 185, no. 3, pp. 1550–1557, 2010.
[35]  G. Gladigau, P. Haselmayer, I. Scharrer et al., “A role for Toll-like receptor mediated signals in neutrophils in the pathogenesis of the antiphospholipid syndrome,” PLoS ONE, vol. 7, no. 7, Article ID e42176, 2012.
[36]  I. Shapira, D. Andrade, S. L. Allen, and J. E. Salmon, “Brief report: induction of sustained resion in recurrent catastrophic antiphospholipid syndrome via inhibition of terminal complement with eculizumab,” Arthritis & Rheumatism, vol. 64, no. 8, pp. 2719–2723, 2012.
[37]  M. Blank, L. Baraam, M. Eisenstein et al., “β2-Glycoprotein-I based peptide regulate endothelial-cells tissue-factor expression via negative regulation of pGSK3β expression and reduces experimental-antiphospholipid-syndrome,” Journal of Autoimmunity, vol. 37, no. 1, pp. 8–17, 2011.

Full-Text

comments powered by Disqus